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Publisher: Elsevier   (Total: 3043 journals)

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Showing 1 - 200 of 3043 Journals sorted alphabetically
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 22, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 21, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 84, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 25, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 30, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 4)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 5, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 356, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 25, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 1)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 234, SJR: 3.683, h-index: 202)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.615, h-index: 21)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.442, h-index: 21)
Acta Oecologica     Hybrid Journal   (Followers: 10, SJR: 0.915, h-index: 53)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription   (Followers: 1)
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 3, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 2)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 23, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 4)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 3)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 4, SJR: 0.383, h-index: 19)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 2)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 5, SJR: 0.141, h-index: 3)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 4, SJR: 0.112, h-index: 2)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 4)
Acute Pain     Full-text available via subscription   (Followers: 13)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.967, h-index: 57)
Addictive Behaviors     Hybrid Journal   (Followers: 15, SJR: 1.514, h-index: 92)
Addictive Behaviors Reports     Open Access   (Followers: 5)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 21)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 135, SJR: 5.2, h-index: 222)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.265, h-index: 53)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.299, h-index: 15)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, SJR: 2.071, h-index: 82)
Advances in Anesthesia     Full-text available via subscription   (Followers: 25, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 6, SJR: 1.054, h-index: 35)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 22, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 3.31, h-index: 42)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.277, h-index: 43)
Advances in Botanical Research     Full-text available via subscription   (Followers: 3, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 25, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 26, SJR: 0.183, h-index: 23)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.665, h-index: 29)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 9, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 29, SJR: 0.938, h-index: 33)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18, SJR: 2.314, h-index: 130)
Advances in Computers     Full-text available via subscription   (Followers: 16, SJR: 0.223, h-index: 22)
Advances in Dermatology     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 6)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Ecological Research     Full-text available via subscription   (Followers: 41, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 25, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 41, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 3)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 50, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Genetics     Full-text available via subscription   (Followers: 15, SJR: 2.558, h-index: 54)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 2.325, h-index: 20)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 22, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 0.497, h-index: 31)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.396, h-index: 27)
Advances in Immunology     Full-text available via subscription   (Followers: 35, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 1.132, h-index: 42)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 3, SJR: 1.274, h-index: 27)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 2)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 9)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16, SJR: 1.645, h-index: 45)
Advances in Mathematics     Full-text available via subscription   (Followers: 10, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6, SJR: 0.489, h-index: 25)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.324, h-index: 8)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 3)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15, SJR: 2.885, h-index: 45)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.148, h-index: 11)
Advances in Parasitology     Full-text available via subscription   (Followers: 7, SJR: 2.37, h-index: 73)
Advances in Pediatrics     Full-text available via subscription   (Followers: 24, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 13)
Advances in Pharmacology     Full-text available via subscription   (Followers: 15, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 8)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 4)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 61)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5, SJR: 0.478, h-index: 32)
Advances in Radiation Oncology     Open Access  
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.1, h-index: 2)
Advances in Space Research     Full-text available via subscription   (Followers: 355, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 8)
Advances in Surgery     Full-text available via subscription   (Followers: 7, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 30, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 17)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 44, SJR: 2.408, h-index: 94)
Aeolian Research     Hybrid Journal   (Followers: 5, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 326, SJR: 0.816, h-index: 49)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.318, h-index: 36)
African J. of Emergency Medicine     Open Access   (Followers: 5, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 8, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 406, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 16, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 30, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 39, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 1)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 54, SJR: 1.879, h-index: 120)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.434, h-index: 14)
Air Medical J.     Hybrid Journal   (Followers: 5, SJR: 0.234, h-index: 18)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.285, h-index: 3)
Alcohol     Hybrid Journal   (Followers: 11, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 8)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.436, h-index: 12)
Alexandria J. of Medicine     Open Access  
Algal Research     Partially Free   (Followers: 8, SJR: 2.05, h-index: 20)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.46, h-index: 29)
Allergology Intl.     Open Access   (Followers: 4, SJR: 0.776, h-index: 35)
Alpha Omegan     Full-text available via subscription   (SJR: 0.121, h-index: 9)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 8, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 48, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 6)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 49, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 47, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 39, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 8, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 15, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 31, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 25, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 32, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 45, SJR: 2.023, h-index: 189)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 231, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 58, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.249, h-index: 88)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 26, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 22, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 34, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 5)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 57, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 11)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 2, SJR: 0.209, h-index: 27)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription   (SJR: 0.104, h-index: 3)
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 4, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 37, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 168, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 8, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 11)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 1)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 22, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access  
Animal Behaviour     Hybrid Journal   (Followers: 161, SJR: 1.907, h-index: 126)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 1.151, h-index: 83)
Animal Reproduction Science     Hybrid Journal   (Followers: 5, SJR: 0.711, h-index: 78)
Annales d'Endocrinologie     Full-text available via subscription   (Followers: 1, SJR: 0.394, h-index: 30)
Annales d'Urologie     Full-text available via subscription  
Annales de Cardiologie et d'Angéiologie     Full-text available via subscription   (SJR: 0.177, h-index: 13)
Annales de Chirurgie de la Main et du Membre Supérieur     Full-text available via subscription  
Annales de Chirurgie Plastique Esthétique     Full-text available via subscription   (Followers: 2, SJR: 0.354, h-index: 22)
Annales de Chirurgie Vasculaire     Full-text available via subscription   (Followers: 1)

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Journal Cover Advances in Pharmacology
  [SJR: 1.718]   [H-I: 58]   [15 followers]  Follow
   Full-text available via subscription Subscription journal
   ISSN (Print) 1054-3589
   Published by Elsevier Homepage  [3043 journals]
  • Receptor Binding Assays and Drug Discovery
    • Authors: David B. Bylund; S.J. Enna
      Abstract: Publication date: Available online 15 October 2017
      Source:Advances in Pharmacology
      Author(s): David B. Bylund, S.J. Enna
      Although Solomon Snyder authored hundreds of research reports and several books covering a broad range of topics in the neurosciences, he is best known by many as the person who developed neurotransmitter receptor radioligand binding assays. By demonstrating the utility of this approach for studying transmitter receptors in brain, Dr. Snyder provided the scientific community with a powerful new tool for identifying and characterizing these sites, for defining their relationship to neurological and psychiatric disorders, and their involvement in mediating the actions of psychotherapeutics. Although it was hoped the receptor binding technique could also be used as a primary screen to speed and simplify the identification of novel drug candidates, experience has taught that ligand binding is most useful for drug discovery when it is used in conjunction with functional, phenotypic assays. The incorporation of ligand binding assays into the drug discovery process played a significant role in altering the search for new therapeutics from solely an empirical undertaking to a mechanistic and hypothesis-driven enterprise. This illustrates the impact of Dr. Snyder's work, not only on neuroscience research but on the discovery, development, and characterization of drugs for treating a variety of medical conditions.

      PubDate: 2017-10-19T03:32:56Z
      DOI: 10.1016/bs.apha.2017.08.007
  • Multiple Pathways Mediate MicroRNA Degradation: Focus on the Translin/Trax
           RNase Complex
    • Authors: Jay Baraban; Aparna Shah Xiuping
      Abstract: Publication date: Available online 4 October 2017
      Source:Advances in Pharmacology
      Author(s): Jay M. Baraban, Aparna Shah, Xiuping Fu
      The discovery of the microRNA system has revolutionized our understanding of translational control. Furthermore, growing appreciation of the pivotal role that de novo translation plays in activity-dependent synaptic plasticity has fueled interest among neuroscientists in deciphering how the microRNA system impacts neuronal signaling and the pathophysiology of neuropsychiatric disorders. Although we have a general understanding of how the microRNA system operates, many key questions remain. In particular, the biosynthesis of microRNAs and their role in translational silencing are fairly well understood. However, much less is known about how microRNAs are degraded and silencing is reversed, crucial aspects of microRNA signaling. In contrast to microRNA synthesis which is mediated almost exclusively by a single pathway that culminates in Dicer, recent studies indicate that there are multiple pathways of microRNA degradation that target different subpopulations of microRNAs. While the Lin-28 pathway of microRNA degradation has been investigated extensively, the translin/trax RNase complex has emerged recently as another pathway mediating microRNA degradation. Accordingly, we summarize herein key features of the translin/trax RNase complex as well as important gaps in our understanding of its regulation and function that are the focus of ongoing studies.

      PubDate: 2017-10-05T20:13:18Z
  • Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease
    • Authors: Xi Wang; Raouf A. Khalil
      Abstract: Publication date: Available online 19 September 2017
      Source:Advances in Pharmacology
      Author(s): Xi Wang, Raouf A. Khalil
      Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that degrade various proteins in the extracellular matrix (ECM). Typically, MMPs have a propeptide sequence, a catalytic metalloproteinase domain with catalytic zinc, a hinge region or linker peptide, and a hemopexin domain. MMPs are commonly classified on the basis of their substrates and the organization of their structural domains into collagenases, gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs, and other MMPs. MMPs are secreted by many cells including fibroblasts, vascular smooth muscle (VSM), and leukocytes. MMPs are regulated at the level of mRNA expression and by activation through removal of the propeptide domain from their latent zymogen form. MMPs are often secreted in an inactive proMMP form, which is cleaved to the active form by various proteinases including other MMPs. MMPs degrade various protein substrates in ECM including collagen and elastin. MMPs could also influence endothelial cell function as well as VSM cell migration, proliferation, Ca2+ signaling, and contraction. MMPs play a role in vascular tissue remodeling during various biological processes such as angiogenesis, embryogenesis, morphogenesis, and wound repair. Alterations in specific MMPs could influence arterial remodeling and lead to various pathological disorders such as hypertension, preeclampsia, atherosclerosis, aneurysm formation, as well as excessive venous dilation and lower extremity venous disease. MMPs are often regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP ratio often determines the extent of ECM protein degradation and tissue remodeling. MMPs may serve as biomarkers and potential therapeutic targets for certain vascular disorders.

      PubDate: 2017-09-22T05:21:38Z
      DOI: 10.1016/bs.apha.2017.08.002
  • The Dynamic Actin Cytoskeleton in Smooth Muscle
    • Authors: Dale D. Tang
      Abstract: Publication date: Available online 24 August 2017
      Source:Advances in Pharmacology
      Author(s): Dale D. Tang
      Smooth muscle contraction requires both myosin activation and actin cytoskeletal remodeling. Actin cytoskeletal reorganization facilitates smooth muscle contraction by promoting force transmission between the contractile unit and the extracellular matrix (ECM), and by enhancing intercellular mechanical transduction. Myosin may be viewed to serve as an “engine” for smooth muscle contraction whereas the actin cytoskeleton may function as a “transmission system” in smooth muscle. The actin cytoskeleton in smooth muscle also undergoes restructuring upon activation with growth factors or the ECM, which controls smooth muscle cell proliferation and migration. Abnormal smooth muscle contraction, cell proliferation, and motility contribute to the development of vascular and pulmonary diseases. A number of actin-regulatory proteins including protein kinases have been discovered to orchestrate actin dynamics in smooth muscle. In particular, Abelson tyrosine kinase (c-Abl) is an important molecule that controls actin dynamics, contraction, growth, and motility in smooth muscle. Moreover, c-Abl coordinates the regulation of blood pressure and contributes to the pathogenesis of airway hyperresponsiveness and vascular/airway remodeling in vivo. Thus, c-Abl may be a novel pharmacological target for the development of new therapy to treat smooth muscle diseases such as hypertension and asthma.

      PubDate: 2017-08-30T19:30:10Z
      DOI: 10.1016/bs.apha.2017.06.001
  • Cannabinoids in the Cardiovascular System
    • Authors: Wing S.V. Ho; Melanie E.M. Kelly
      Abstract: Publication date: Available online 3 July 2017
      Source:Advances in Pharmacology
      Author(s): Wing S.V. Ho, Melanie E.M. Kelly
      Cannabinoids are known to modulate cardiovascular functions including heart rate, vascular tone, and blood pressure in humans and animal models. Essential components of the endocannabinoid system, namely, the production, degradation, and signaling pathways of endocannabinoids have been described not only in the central and peripheral nervous system but also in myocardium, vasculature, platelets, and immune cells. The mechanisms of cardiovascular responses to endocannabinoids are often complex and may involve cannabinoid CB1 and CB2 receptors or non-CB1/2 receptor targets. Preclinical and some clinical studies have suggested that targeting the endocannabinoid system can improve cardiovascular functions in a number of pathophysiological conditions, including hypertension, metabolic syndrome, sepsis, and atherosclerosis. In this chapter, we summarize the local and systemic cardiovascular effects of cannabinoids and highlight our current knowledge regarding the therapeutic potential of endocannabinoid signaling and modulation.

      PubDate: 2017-07-06T03:14:03Z
      DOI: 10.1016/bs.apha.2017.05.002
  • Endocannabinoid Analytical Methodologies: Techniques That Drive
           Discoveries That Drive Techniques
    • Authors: Fabiana Piscitelli; Heather B. Bradshaw
      Abstract: Publication date: Available online 3 July 2017
      Source:Advances in Pharmacology
      Author(s): Fabiana Piscitelli, Heather B. Bradshaw
      Identification of the two major endogenous cannabinoid ligands, known as endocannabinoids, N-arachidonoyl-ethanolamine (anandamide, AEA) and 2-arachidonoyl-glycerol (2-AG), opened the way for the identification and isolation of other lipid congeners, all derivatives of fatty acids and related to the Endocannabinoid System. The nomenclature of this anandamide-type class of lipids is evolving as new species are discovered all the time. However, they each fall under the larger umbrella of lipids that are a conjugation of a fatty acid with an amine through and amide bond, which we will refer to as lipoamines. Specific subspecies of lipoamines that have been discovered are the N-acyl-ethanolamides (including AEA), N-acyl-dopamines, N-acyl-serotonins, N-acyl-GABA, N-acyl-taurines, and a growing number of N-acyl amino acids. Emerging data from multiple labs also show that monoacylglycerols (including 2-AG), COX-2 metabolites, and fatty acid esters of hydroxyl fatty acids are interconnected with these lipoamines at both the biosynthetic and metabolic levels. Understanding the molecular relatedness of these lipids is important for studying how they act as signaling molecules; however, a first step in this process hinges on advances in being able to accurately measure them.

      PubDate: 2017-07-06T03:14:03Z
      DOI: 10.1016/bs.apha.2017.04.003
  • Spicing Up Pharmacology: A Review of Synthetic Cannabinoids From Structure
           to Adverse Events
    • Authors: Colin Davidson; Jolanta Opacka-Juffry; Angel Arevalo-Martin; Daniel Garcia-Ovejero; Eduardo Molina-Holgado; Francisco Molina-Holgado
      Abstract: Publication date: Available online 20 June 2017
      Source:Advances in Pharmacology
      Author(s): Colin Davidson, Jolanta Opacka-Juffry, Angel Arevalo-Martin, Daniel Garcia-Ovejero, Eduardo Molina-Holgado, Francisco Molina-Holgado
      Recreational use of synthetic cannabinoids (SCB), a class of novel psychoactive substances is an increasing public health problem specifically in Western societies, with teenagers, young adults, and the prison population being the most affected. Some of these SCB are analogs of tetrahydrocannabinol, aminoalkylindoles, and other phytocannabinoid analogs have been detected in herbal preparations generically called “Spice.” Spice, “K2” or “fake cannabis” is a general term used for variable herbal mixtures of unknown ingredients or chemical composition. SCB are highly potent CB1 cannabinoid receptor agonists falsely marketed and sold as safe and legal drugs. Here, we present an overview of the endocannabinoid system, CB, and SCB chemical structures and activity at CB receptors. Finally, we highlight the psychological effects of SCB, particularly on learning and memory, and adverse clinical effects including on the cardiovascular system, kidneys, and CNS, including psychosis. Taken together, it is clear that many SCB are extremely dangerous and a major public health problem.

      PubDate: 2017-06-27T01:01:12Z
      DOI: 10.1016/bs.apha.2017.05.001
  • Cannabinoids and Pain: Sites and Mechanisms of Action
    • Authors: Katarzyna Starowicz; David P. Finn
      Abstract: Publication date: Available online 20 June 2017
      Source:Advances in Pharmacology
      Author(s): Katarzyna Starowicz, David P. Finn
      The endocannabinoid system, consisting of the cannabinoid1 receptor (CB1R) and cannabinoid2 receptor (CB2R), endogenous cannabinoid ligands (endocannabinoids), and metabolizing enzymes, is present throughout the pain pathways. Endocannabinoids, phytocannabinoids, and synthetic cannabinoid receptor agonists have antinociceptive effects in animal models of acute, inflammatory, and neuropathic pain. CB1R and CB2R located at peripheral, spinal, or supraspinal sites are important targets mediating these antinociceptive effects. The mechanisms underlying the analgesic effects of cannabinoids likely include inhibition of presynaptic neurotransmitter and neuropeptide release, modulation of postsynaptic neuronal excitability, activation of the descending inhibitory pain pathway, and reductions in neuroinflammatory signaling. Strategies to dissociate the psychoactive effects of cannabinoids from their analgesic effects have focused on peripherally restricted CB1R agonists, CB2R agonists, inhibitors of endocannabinoid catabolism or uptake, and modulation of other non-CB1R/non-CB2R targets of cannabinoids including TRPV1, GPR55, and PPARs. The large body of preclinical evidence in support of cannabinoids as potential analgesic agents is supported by clinical studies demonstrating their efficacy across a variety of pain disorders.

      PubDate: 2017-06-27T01:01:12Z
      DOI: 10.1016/bs.apha.2017.05.003
  • Cannabinoid Receptor-Related Orphan G Protein-Coupled Receptors
    • Authors: Andrew Irving; Ghayth Abdulrazzaq; Sue L.F. Chan; June Penman; Jenni Harvey; Stephen P.H. Alexander
      Abstract: Publication date: Available online 12 June 2017
      Source:Advances in Pharmacology
      Author(s): Andrew Irving, Ghayth Abdulrazzaq, Sue L.F. Chan, June Penman, Jenni Harvey, Stephen P.H. Alexander
      Of the druggable group of G protein-coupled receptors in the human genome, a number remain which have yet to be paired with an endogenous ligand—orphan GPCRs. Among these 100 or so entities, 3 have been linked to the cannabinoid system. GPR18, GPR55, and GPR119 exhibit limited sequence homology with the established CB1 and CB2 cannabinoid receptors. However, the pharmacology of these orphan receptors displays overlap with CB1 and CB2 receptors, particularly for GPR18 and GPR55. The linking of GPR119 to the cannabinoid receptors is less convincing and emanates from structural similarities of endogenous ligands active at these GPCRs, but which do not cross-react. This review describes the evidence for describing these orphan GPCRs as cannabinoid receptor-like receptors.

      PubDate: 2017-06-14T21:32:46Z
      DOI: 10.1016/bs.apha.2017.04.004
  • Actions and Regulation of Ionotropic Cannabinoid Receptors
    • Authors: Luciano De Petrocellis; Massimo Nabissi; Giorgio Santoni; Alessia Ligresti
      Abstract: Publication date: Available online 12 June 2017
      Source:Advances in Pharmacology
      Author(s): Luciano De Petrocellis, Massimo Nabissi, Giorgio Santoni, Alessia Ligresti
      Almost three decades have passed since the identification of the two specific metabotropic receptors mediating cannabinoid pharmacology. Thereafter, many cannabinoid effects, both at central and peripheral levels, have been well documented and characterized. However, numerous evidences demonstrated that these pharmacological actions could not be attributable solely to the activation of CB1 and CB2 receptors since several important cannabimimetic actions have been found in biological systems lacking CB1 or CB2 gene such as in specific cell lines or transgenic mice. It is now well accepted that, beyond their receptor-mediated effects, these molecules can act also via CB1/CB2-receptor-independent mechanism. Cannabinoids have been demonstrated to modulate several voltage-gated channels (including Ca2+, Na+, and various type of K+ channels), ligand-gated ion channels (i.e., GABA, glycine), and ion-transporting membranes proteins such as transient potential receptor class (TRP) channels. The first direct, cannabinoid receptor-independent interaction was reported on the function of serotonin 5-HT3 receptor-ion channel complex. Similar effects were reported also on the other above mentioned ion channels. In the early ninety, studies searching for endogenous modulators of L-type Ca2+ channels identified anandamide as ligand for L-type Ca2+ channel. Later investigations indicated that other types of Ca2+ currents are also affected by endocannabinoids, and, in the late ninety, it was discovered that endocannabinoids activate the vanilloid receptor subtype 1 (TRPV1), and nowadays, it is known that (endo)cannabinoids gate at least five distinct TRP channels. This chapter focuses on cannabinoid regulation of ion channels and lays special emphasis on their action at transient receptor channels.

      PubDate: 2017-06-14T21:32:46Z
      DOI: 10.1016/bs.apha.2017.04.001
  • CB1 and CB2 Receptor Pharmacology
    • Authors: Allyn C. Howlett; Mary E. Abood
      Abstract: Publication date: Available online 12 June 2017
      Source:Advances in Pharmacology
      Author(s): Allyn C. Howlett, Mary E. Abood
      The CB1 and CB2 cannabinoid receptors (CB1R, CB2R) are members of the G protein-coupled receptor (GPCR) family that were identified over 20 years ago. CB1Rs and CB2Rs mediate the effects of Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive constituent of marijuana, and subsequently identified endogenous cannabinoids (endocannabinoids) anandamide and 2-arachidonoyl glycerol. CB1Rs and CB2Rs have both similarities and differences in their pharmacology. Both receptors recognize multiple classes of agonist and antagonist compounds and produce an array of distinct downstream effects. Natural polymorphisms and alternative splice variants may also contribute to their pharmacological diversity. As our knowledge of the distinct differences grows, we may be able to target select receptor conformations and their corresponding pharmacological responses. This chapter will discuss their pharmacological characterization, distribution, phylogeny, and signaling pathways. In addition, the effects of extended agonist exposure and how that affects signaling and expression patterns of the receptors are considered.

      PubDate: 2017-06-14T21:32:46Z
      DOI: 10.1016/bs.apha.2017.03.007
  • Cannabinoids as Anticancer Drugs
    • Authors: Robert Ramer; Burkhard Hinz
      Abstract: Publication date: Available online 12 June 2017
      Source:Advances in Pharmacology
      Author(s): Robert Ramer, Burkhard Hinz
      The endocannabinoid system encompassing cannabinoid receptors, endogenous receptor ligands (endocannabinoids), as well as enzymes conferring the synthesis and degradation of endocannabinoids has emerged as a considerable target for pharmacotherapeutical approaches of numerous diseases. Besides palliative effects of cannabinoids used in cancer treatment, phytocannabinoids, synthetic agonists, as well as substances that increase endogenous endocannabinoid levels have gained interest as potential agents for systemic cancer treatment. Accordingly, cannabinoid compounds have been reported to inhibit tumor growth and spreading in numerous rodent models. The underlying mechanisms include induction of apoptosis, autophagy, and cell cycle arrest in tumor cells as well as inhibition of tumor cell invasion and angiogenic features of endothelial cells. In addition, cannabinoids have been shown to suppress epithelial-to-mesenchymal transition, to enhance tumor immune surveillance, and to support chemotherapeutics’ effects on drug-resistant cancer cells. However, unwanted side effects include psychoactivity and possibly pathogenic effects on liver health. Other cannabinoids such as the nonpsychoactive cannabidiol exert a comparatively good safety profile while exhibiting considerable anticancer properties. So far experience with anticarcinogenic effects of cannabinoids is confined to in vitro studies and animal models. Although a bench-to-bedside conversion remains to be established, the current knowledge suggests cannabinoid compounds to serve as a group of drugs that may offer significant advantages for patients suffering from cancer diseases. The present review summarizes the role of the endocannabinoid system and cannabinoid compounds in tumor progression.

      PubDate: 2017-06-14T21:32:46Z
      DOI: 10.1016/bs.apha.2017.04.002
  • Is the Cannabinoid CB2 Receptor a Major Regulator of the Neuroinflammatory
           Axis of the Neurovascular Unit in Humans'
    • Authors: Dan T. Kho; Michelle Glass; Euan S. Graham
      Abstract: Publication date: Available online 12 June 2017
      Source:Advances in Pharmacology
      Author(s): Dan T. Kho, Michelle Glass, Euan S. Graham
      The central nervous system (CNS) is an immune privileged site where the neurovascular unit (NVU) and the blood–brain barrier (BBB) act as a selectively permeable interface to control the passage of nutrients and inflammatory cells into the brain parenchyma. However, in response to injury, infection, or disease, CNS cells become activated, and release inflammatory mediators to recruit immune cells to the site of inflammation. Increasing evidence suggests that cannabinoids may have a neuroprotective role in CNS inflammatory conditions. For many years, it was widely accepted that cannabinoid receptor type 1 (CB1) modulates neurological function centrally, while peripheral cannabinoid receptor type 2 (CB2) modulates immune function. As knowledge about the physiology and pharmacology of the endocannabinoid system advances, there is increasing interest in targeting CB2 as a potential treatment for inflammation-dependent CNS diseases (Ashton & Glass, 2007), where recent rodent and human studies have implicated intervention at the level of the NVU and BBB. These are incredibly important in brain health and disease. Therefore, this review begins by explaining the cellular and molecular components of these systems, highlighting important molecules potentially regulated by cannabinoid ligands and then takes an unbiased look at the evidence in support (or otherwise) of cannabinoid receptor expression and control of the NVU and BBB function in humans.

      PubDate: 2017-06-14T21:32:46Z
      DOI: 10.1016/bs.apha.2017.03.009
  • Functional Selectivity at Cannabinoid Receptors
    • Authors: Richard Priestley; Michelle Glass; David Kendall
      Abstract: Publication date: Available online 5 June 2017
      Source:Advances in Pharmacology
      Author(s): Richard Priestley, Michelle Glass, David Kendall
      It is now clear that, in contrast to traditional descriptions of G protein-coupled receptor signaling, agonists can activate or inhibit characteristic patterns of downstream effector pathways depending on their structures and the conformational changes induced in the receptor. This is referred to as functional selectivity (also known as agonist-directed trafficking, ligand-induced differential signaling, or biased agonism). It is important because even small structural differences can result in significant variations in overall agonist effects (wanted and unwanted) depending on which postreceptor signaling systems are engaged by each agonist/receptor pairing. In addition to the canonical signaling pathways mediated by Gi/o proteins, CB1 and CB2 receptor agonists can have effects via differential activation not only of Gi subtypes but also of Gs and Gq/11 proteins. For example, the classical cannabinoid HU-210 produces maximal activation of both Gi and Go proteins, while the endocannabinoid anandamide and aminoalkylindole WIN 55,212 both produce maximal activation of Gi, but submaximal activation of Go. Cannabinoid agonists can also signal differentially via β-arrestins coupled to mitogen-activated protein kinases, subsequently promoting varying degrees of receptor internalization and agonist desensitization. A recent extensive characterization of the molecular pharmacology of CB2 agonists (Soethoudt et al., 2017) identified marked differences (bias) in the ability of certain agonists to activate distinct signaling pathways (cAMP accumulation, ERK phosphorylation, GIRK activation, GTPγS binding, and β-arrestin recruitment) and to cause off-target effects, exemplifying the need to evaluate functional selectivity in agonist drug development.

      PubDate: 2017-06-09T20:15:31Z
      DOI: 10.1016/bs.apha.2017.03.005
  • Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads
    • Authors: Ethan B. Russo; Jahan Marcu
      Abstract: Publication date: Available online 5 June 2017
      Source:Advances in Pharmacology
      Author(s): Ethan B. Russo, Jahan Marcu
      The golden age of cannabis pharmacology began in the 1960s as Raphael Mechoulam and his colleagues in Israel isolated and synthesized cannabidiol, tetrahydrocannabinol, and other phytocannabinoids. Initially, THC garnered most research interest with sporadic attention to cannabidiol, which has only rekindled in the last 15 years through a demonstration of its remarkably versatile pharmacology and synergy with THC. Gradually a cognizance of the potential of other phytocannabinoids has developed. Contemporaneous assessment of cannabis pharmacology must be even far more inclusive. Medical and recreational consumers alike have long believed in unique attributes of certain cannabis chemovars despite their similarity in cannabinoid profiles. This has focused additional research on the pharmacological contributions of mono- and sesquiterpenoids to the effects of cannabis flower preparations. Investigation reveals these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant. Synergistic relationships of the terpenoids to cannabinoids will be highlighted and include many complementary roles to boost therapeutic efficacy in treatment of pain, psychiatric disorders, cancer, and numerous other areas. Additional parts of the cannabis plant provide a wide and distinct variety of other compounds of pharmacological interest, including the triterpenoid friedelin from the roots, canniprene from the fan leaves, cannabisin from seed coats, and cannflavin A from seed sprouts. This chapter will explore the unique attributes of these agents and demonstrate how cannabis may yet fulfil its potential as Mechoulam's professed “pharmacological treasure trove.”

      PubDate: 2017-06-09T20:15:31Z
      DOI: 10.1016/bs.apha.2017.03.004
  • The Role of Nuclear Hormone Receptors in Cannabinoid Function
    • Authors: Marco Pistis; Saoirse E. O'Sullivan
      Abstract: Publication date: Available online 25 May 2017
      Source:Advances in Pharmacology
      Author(s): Marco Pistis, Saoirse E. O'Sullivan
      Since the early 2000s, evidence has been accumulating that most cannabinoid compounds interact with the nuclear hormone family peroxisome proliferator-activated receptors (PPARs). This can be through direct binding of these compounds to PPARs, metabolism of cannabinoid to other PPAR-activating chemicals, or indirect activation of PPAR through cell signaling pathways. Delivery of cannabinoids to the nucleus may be facilitated by fatty acid-binding proteins and carrier proteins. All PPAR isoforms appear to be activated by cannabinoids, but the majority of evidence is for PPARα and γ. To date, little is known about the potential interaction of cannabinoids with other nuclear hormones. At least some (but not all) of the well-known biological actions of cannabinoids including neuroprotection, antiinflammatory action, and analgesic effects are partly mediated by PPAR-activation, often in combination with activation of the more traditional target sites of action. This has been best investigated for the endocannabinoid-like compounds palmitoylethanolamide and oleoylethanolamine acting at PPARα, and for phytocannabinoids or their derivatives activation acting at PPARγ. However, there are still many aspects of cannabinoid activation of PPAR and the role it plays in the biological and therapeutic effects of cannabinoids that remain to be investigated.

      PubDate: 2017-05-30T18:00:57Z
      DOI: 10.1016/bs.apha.2017.03.008
  • Endocannabinoid Turnover
    • Authors: Christopher J. Fowler; Patrick Doherty; Stephen P.H. Alexander
      Abstract: Publication date: Available online 25 May 2017
      Source:Advances in Pharmacology
      Author(s): Christopher J. Fowler, Patrick Doherty, Stephen P.H. Alexander
      In this review, we consider the biosynthetic, hydrolytic, and oxidative metabolism of the endocannabinoids anandamide and 2-arachidonoylglycerol. We describe the enzymes associated with these events and their characterization. We identify the inhibitor profile for these enzymes and the status of therapeutic exploitation, which to date has been limited to clinical trials for fatty acid amide hydrolase inhibitors. To bring the review to a close, we consider whether point block of a single enzyme is likely to be the most successful approach for therapeutic exploitation of the endocannabinoid system.

      PubDate: 2017-05-30T18:00:57Z
      DOI: 10.1016/bs.apha.2017.03.006
  • GABAA Receptors and the Diversity in their Structure and Pharmacology
    • Authors: Han Chow Chua; Mary Chebib
      Abstract: Publication date: Available online 2 May 2017
      Source:Advances in Pharmacology
      Author(s): Han Chow Chua, Mary Chebib
      GABAA receptors (GABAARs) are a class of ligand-gated ion channels with high physiological and therapeutic significance. In the brain, these pentameric receptors occur with diverse subunit composition, which confers highly complex pharmacology to this receptor class. An impressive range of clinically used therapeutics are known to bind to distinct sites found on GABAARs to modulate receptor function. Numerous experimental approaches have been used over the years to elucidate the binding sites of these drugs, but unequivocal identification is challenging due to subtype- and ligand-dependent pharmacology. Here, we review the current structural and pharmacological understanding of GABAARs, besides highlighting recent evidence which has revealed greater complexity than previously anticipated.

      PubDate: 2017-05-06T12:06:12Z
      DOI: 10.1016/bs.apha.2017.03.003
  • Modulation of Ion Channels by Cysteine-Rich Peptides: From Sequence to
    • Authors: Mehdi Mobli; Eivind A.B. Undheim; Lachlan D. Rash
      Abstract: Publication date: Available online 24 April 2017
      Source:Advances in Pharmacology
      Author(s): Mehdi Mobli, Eivind A.B. Undheim, Lachlan D. Rash
      Venom peptides are natural ligands of ion channels and have been used extensively in pharmacological characterization of various ion channels and receptors. In this chapter, we survey all known venom peptide ion-channel modulators. Our survey reveals that the majority of venom peptides characterized to date target voltage-gated sodium or potassium channels. We further find that the majority of these peptides are found in scorpion and spider venoms. We discuss the influence of the pharmacological tools available in biasing discovery and the classical “toxin-to-sequence” approach to venom peptide biodiscovery. The impact of high-throughput sequencing on the existing discovery framework is likely to be significant and we propose here an alternative “sequence-to-toxin” approach to peptide screening, relying more on recently developed high-throughput methods. Methods for production and characterization of disulfide rich toxins in a high-throughput setting are then described, focusing on bacterial protein expression and solution state structural characterization by NMR spectroscopy. Finally, the role of X-ray crystallography and cryo-EM are highlighted by discussing the currently known channel-peptide complexes.

      PubDate: 2017-04-30T11:10:05Z
      DOI: 10.1016/bs.apha.2017.03.001
  • Role of Nonneuronal TRPV4 Signaling in Inflammatory Processes
    • Authors: Pradeep Rajasekhar; Daniel P. Poole; Nicholas A. Veldhuis
      Abstract: Publication date: Available online 24 April 2017
      Source:Advances in Pharmacology
      Author(s): Pradeep Rajasekhar, Daniel P. Poole, Nicholas A. Veldhuis
      Transient receptor potential (TRP) ion channels are important signaling components in nociceptive and inflammatory pathways. This is attributed to their ability to function as polymodal sensors of environmental stimuli (chemical and mechanical) and as effector molecules in receptor signaling pathways. TRP vanilloid 4 (TRPV4) is a nonselective cation channel that is activated by multiple endogenous stimuli including shear stress, membrane stretch, and arachidonic acid metabolites. TRPV4 contributes to many important physiological processes and dysregulation of its activity is associated with chronic conditions of metabolism, inflammation, peripheral neuropathies, musculoskeletal development, and cardiovascular regulation. Mechanosensory and receptor- or lipid-mediated signaling functions of TRPV4 have historically been attributed to central and peripheral neurons. However, with the development of potent and selective pharmacological tools, transgenic mice and improved molecular and imaging techniques, many new roles for TRPV4 have been revealed in nonneuronal cells. In this chapter, we discuss these recent findings and highlight the need for greater characterization of TRPV4-mediated signaling in nonneuronal cell types that are either directly associated with neurons or indirectly control their excitability through release of sensitizing cellular factors. We address the integral role of these cells in sensory and inflammatory processes as well as their importance when considering undesirable on-target effects that may be caused by systemic delivery of TRPV4-selective pharmaceutical agents for treatment of chronic diseases. In future, this will drive a need for targeted drug delivery strategies to regulate such a diverse and promiscuous protein.

      PubDate: 2017-04-30T11:10:05Z
      DOI: 10.1016/bs.apha.2017.03.002
  • Sodium Channels and Venom Peptide Pharmacology
    • Authors: Mathilde R. Israel; Bryan Tay; Jennifer R. Deuis; Irina Vetter
      Abstract: Publication date: Available online 8 April 2017
      Source:Advances in Pharmacology
      Author(s): Mathilde R. Israel, Bryan Tay, Jennifer R. Deuis, Irina Vetter
      Venomous animals including cone snails, spiders, scorpions, anemones, and snakes have evolved a myriad of components in their venoms that target the opening and/or closing of voltage-gated sodium channels to cause devastating effects on the neuromuscular systems of predators and prey. These venom peptides, through design and serendipity, have not only contributed significantly to our understanding of sodium channel pharmacology and structure, but they also represent some of the most phyla- and isoform-selective molecules that are useful as valuable tool compounds and drug leads. Here, we review our understanding of the basic function of mammalian voltage-gated sodium channel isoforms as well as the pharmacology of venom peptides that act at these key transmembrane proteins.

      PubDate: 2017-04-30T11:10:05Z
      DOI: 10.1016/bs.apha.2017.01.004
  • Voltage-Gated Sodium Channel Pharmacology: Insights From Molecular
           Dynamics Simulations
    • Authors: Rong Chen; Amanda Buyan; Ben Corry
      Abstract: Publication date: Available online 31 March 2017
      Source:Advances in Pharmacology
      Author(s): Rong Chen, Amanda Buyan, Ben Corry
      Voltage-gated ion channels are the target of a range of naturally occurring toxins and therapeutic drugs. There is a great interest in better understanding how these diverse compounds alter channel function in order to design the next generation of therapeutics that can selectively target one of the channel subtypes found in the body. Since the publication of a number of bacterial sodium channel structures, molecular dynamics simulations have been invaluable in gaining a high resolution understanding where many of these small molecules and toxins bind to the channels, how they find their binding site, and how they can selectively bind to one channel subtype over another. This chapter summarizes these recent studies to highlight what has been learnt about channel pharmacology using computer simulations and to draw out shared conclusions, focusing separately on toxin–channel interactions and small molecule–channel interactions.

      PubDate: 2017-04-30T11:10:05Z
      DOI: 10.1016/bs.apha.2017.02.002
  • Acid-Sensing Ion Channel Pharmacology, Past, Present, and Future …
    • Authors: L.D. Rash
      Abstract: Publication date: Available online 21 March 2017
      Source:Advances in Pharmacology
      Author(s): L.D. Rash
      pH is one of the most strictly controlled parameters in mammalian physiology. An extracellular pH of ~7.4 is crucial for normal physiological processes, and perturbations to this have profound effects on cell function. Acidic microenvironments occur in many physiological and pathological conditions, including inflammation, bone remodeling, ischemia, trauma, and intense synaptic activity. Cells exposed to these conditions respond in different ways, from tumor cells that thrive to neurons that are either suppressed or hyperactivated, often fatally. Acid-sensing ion channels (ASICs) are primary pH sensors in mammals and are expressed widely in neuronal and nonneuronal cells. There are six main subtypes of ASICs in rodents that can form homo- or heteromeric channels resulting in many potential combinations. ASICs are present and activated under all of the conditions mentioned earlier, suggesting that they play an important role in how cells respond to acidosis. Compared to many other ion channel families, ASICs were relatively recently discovered—1997—and there is a substantial lack of potent, subtype-selective ligands that can be used to elucidate their structural and functional properties. In this chapter I cover the history of ASIC channel pharmacology, which began before the proteins were even identified, and describe the current arsenal of tools available, their limitations, and take a glance into the future to predict from where new tools are likely to emerge.

      PubDate: 2017-04-30T11:10:05Z
      DOI: 10.1016/bs.apha.2017.02.001
  • Glycine Receptor Drug Discovery
    • Authors: J.W. Lynch; Y. Zhang; S. Talwar; A. Estrada-Mondragon
      Abstract: Publication date: Available online 21 March 2017
      Source:Advances in Pharmacology
      Author(s): J.W. Lynch, Y. Zhang, S. Talwar, A. Estrada-Mondragon
      Postsynaptic glycine receptor (GlyR) chloride channels mediate inhibitory neurotransmission in the spinal cord and brain stem, although presynaptic and extrasynaptic GlyRs are expressed more widely throughout the brain. In humans, GlyRs are assembled as homo- or heteromeric pentamers of α1–3 and β subunits. GlyR malfunctions have been linked to a range of neurological disorders including hyperekplexia, temporal lobe epilepsy, autism, breathing disorders, and chronic inflammatory pain. Although it is possible that GlyRs may eventually be clinically targeted for a variety of neurological disorders, most research to date has focused on developing GlyR-targeted treatments for chronic pain. Inflammatory pain sensitization is caused by inflammatory mediators downregulating the magnitude of α3 GlyR-mediated inhibitory postsynaptic currents in spinal nociceptive neurons. Consistent with this paradigm, it is now well established that the selective enhancement of α3 GlyR current magnitude is effective in alleviating inflammatory pain. In this review, we briefly describe the physiological roles and pharmacological properties of GlyRs. We then outline the methods commonly used to discover new GlyR-active compounds and review recent progress, in our laboratory and elsewhere, in developing GlyR-targeted analgesics. We conclude that the eventual development of an α3 GlyR-targeted analgesic is an eminently feasible goal. However, in selecting or designing new therapeutic leads, we caution against the automatic exclusion of compounds with potentiating effects on α1 GlyRs. Also, as GlyRs are strongly potentiated by Zn2+ at nanomolar concentrations, we also caution against the identification of false positives caused by contaminating Zn2+ in otherwise pure compound samples.

      PubDate: 2017-04-30T11:10:05Z
      DOI: 10.1016/bs.apha.2017.01.003
  • TRPV1 Channels in Immune Cells and Hematological Malignancies
    • Authors: S.A. Omari; M.J. Adams; D.P. Geraghty
      Abstract: Publication date: Available online 21 March 2017
      Source:Advances in Pharmacology
      Author(s): S.A. Omari, M.J. Adams, D.P. Geraghty
      Transient receptor potential vanilloid-1 (TRPV1) is a member of the TRP family of channels that are responsible for nociceptive, thermal, and mechanical sensations. Originally associated exclusively with sensory neurons, TRPV1 is now known to be present in almost all organs, including cells of the immune system, where TRPV1 has been shown to play a pivotal role in inflammation and immunity. Monocytes, macrophages, and dendritic cells express TRPV1, with both mouse and human studies suggesting that TRPV1 activation protects against endotoxin-induced inflammation. In contrast, TRPV1 (and other TRP channels) appears to be required for T-cell receptor activation by mitogens. Additionally, studies in cell lines derived from hematological and other malignancies suggest altered expression/function of TRPV1 might serve as a target for novel cytotoxic therapies.

      PubDate: 2017-04-30T11:10:05Z
      DOI: 10.1016/bs.apha.2017.01.002
  • Genetically Encoded Calcium Indicators as Probes to Assess the Role of
           Calcium Channels in Disease and for High-Throughput Drug Discovery
    • Authors: J.J. Bassett; G.R. Monteith
      Abstract: Publication date: Available online 6 March 2017
      Source:Advances in Pharmacology
      Author(s): J.J. Bassett, G.R. Monteith
      The calcium ion (Ca2+) is an important signaling molecule implicated in many cellular processes, and the remodeling of Ca2+ homeostasis is a feature of a variety of pathologies. Typical methods to assess Ca2+ signaling in cells often employ small molecule fluorescent dyes, which are sometimes poorly suited to certain applications such as assessment of cellular processes, which occur over long periods (hours or days) or in vivo experiments. Genetically encoded calcium indicators are a set of tools available for the measurement of Ca2+ changes in the cytosol and subcellular compartments, which circumvent some of the inherent limitations of small molecule Ca2+ probes. Recent advances in genetically encoded calcium sensors have greatly increased their ability to provide reliable monitoring of Ca2+ changes in mammalian cells. New genetically encoded calcium indicators have diverse options in terms of targeting, Ca2+ affinity and fluorescence spectra, and this will further enhance their potential use in high-throughput drug discovery and other assays. This review will outline the methods available for Ca2+ measurement in cells, with a focus on genetically encoded calcium sensors. How these sensors will improve our understanding of the deregulation of Ca2+ handling in disease and their application to high-throughput identification of drug leads will also be discussed.

      PubDate: 2017-03-07T23:01:09Z
      DOI: 10.1016/bs.apha.2017.01.001
  • Physiology and Pharmacology of Ryanodine Receptor Calcium Release Channels
    • Authors: A.F. Dulhunty; P.G. Board; N.A. Beard; M.G. Casarotto
      Abstract: Publication date: Available online 22 February 2017
      Source:Advances in Pharmacology
      Author(s): A.F. Dulhunty, P.G. Board, N.A. Beard, M.G. Casarotto
      Ryanodine receptor (RyR) ion channels are essential for skeletal and cardiac muscle function. Their knockout leads to perinatal death from respiratory and cardiac failure. Acquired changes or mutations in the protein cause debilitating skeletal myopathy and cardiac arrhythmia which can be deadly. Knowledge of the pharmacology of RyR channels is central to developing effective and specific treatments of these myopathies. The ion channel is a >2.2MDa homotetamer with distinct structural and functional characteristics giving rise to a myriad of regulatory sites that are potential therapeutic targets. Australian researchers have been intimately involved in the exploration of the proteins since their identification in the mid-1980s. We discuss major aspects of RyR physiology and pharmacology that have been tackled in Australian laboratories. Specific areas of interest include ultrastructural aspects and mechanisms of RyR activation in excitation–contraction (EC) coupling and related pharmacological developments, regulation of RyRs by divalent cations, by associated proteins including the FK506-binding proteins, by redox factors and phosphorylation. We consider adverse effects of anthracycline chemotherapeutic drugs on cardiac RyRs. Phenotypes associated with RyR mutations are discussed with current and developing therapeutic approaches for treating the underlying RyR dysfunction.

      PubDate: 2017-02-28T21:54:45Z
      DOI: 10.1016/bs.apha.2016.12.001
  • Nanojunctions of the Sarcoplasmic Reticulum Deliver Site- and
           Function-Specific Calcium Signaling in Vascular Smooth Muscles
    • Authors: A. Mark Evans
      Abstract: Publication date: Available online 2 December 2016
      Source:Advances in Pharmacology
      Author(s): A. Mark Evans
      Vasoactive agents may induce myocyte contraction, dilation, and the switch from a contractile to a migratory–proliferative phenotype(s), which requires changes in gene expression. These processes are directed, in part, by Ca2+ signals, but how different Ca2+ signals are generated to select each function is enigmatic. We have previously proposed that the strategic positioning of Ca2+ pumps and release channels at membrane–membrane junctions of the sarcoplasmic reticulum (SR) demarcates cytoplasmic nanodomains, within which site- and function-specific Ca2+ signals arise. This chapter will describe how nanojunctions of the SR may: (1) define cytoplasmic nanospaces about the plasma membrane, mitochondria, contractile myofilaments, lysosomes, and the nucleus; (2) provide for functional segregation by restricting passive diffusion and by coordinating active ion transfer within a given nanospace via resident Ca2+ pumps and release channels; (3) select for contraction, relaxation, and/or changes in gene expression; and (4) facilitate the switch in myocyte phenotype through junctional reorganization. This should serve to highlight the need for further exploration of cellular nanojunctions and the mechanisms by which they operate, that will undoubtedly open up new therapeutic horizons.

      PubDate: 2016-12-05T07:17:14Z
      DOI: 10.1016/bs.apha.2016.10.001
  • Rho-Mancing to Sensitize Calcium Signaling for Contraction in the
           Vasculature: Role of Rho Kinase
    • Authors: T. Szasz; R.C. Webb
      Abstract: Publication date: Available online 27 October 2016
      Source:Advances in Pharmacology
      Author(s): T. Szasz, R.C. Webb
      Vascular smooth muscle contraction is an important physiological process contributing to cardiovascular homeostasis. The principal determinant of smooth muscle contraction is the intracellular free Ca2+ concentration, and phosphorylation of myosin light chain (MLC) by activated myosin light chain kinase (MLCK) in response to increased Ca2+ is the main pathway by which vasoconstrictor stimuli induce crossbridge cycling of myosin and actin filaments. A secondary pathway for vascular smooth muscle contraction that is not directly dependent on Ca2+ concentration, but rather mediating Ca2+ sensitization, is the RhoA/Rho kinase pathway. In response to contractile stimuli, the small GTPase RhoA activates its downstream effector Rho kinase which, in turn, promotes contraction via myosin light chain phosphatase (MLCP) inhibition. RhoA/Rho kinase-mediated MLCP inhibition occurs mainly by phosphorylation and inhibition of MYPT1, the regulatory subunit of MLCP, or by CPI-17-mediated inhibition of the catalytic subunit of MLCP. In this review, we describe the molecular mechanisms underlying the pivotal role exerted by Rho kinase on vascular smooth muscle contraction and discuss the main regulatory pathways for its activity.

      PubDate: 2016-10-31T14:54:42Z
      DOI: 10.1016/bs.apha.2016.09.001
  • Vascular Cells in Blood Vessel Wall Development and Disease
    • Authors: R. Mazurek; J.M. Dave; R.R. Chandran; A. Misra; A.Q. Sheikh; D.M. Greif
      Abstract: Publication date: Available online 14 October 2016
      Source:Advances in Pharmacology
      Author(s): R. Mazurek, J.M. Dave, R.R. Chandran, A. Misra, A.Q. Sheikh, D.M. Greif
      The vessel wall is composed of distinct cellular layers, yet communication among individual cells within and between layers results in a dynamic and versatile structure. The morphogenesis of the normal vascular wall involves a highly regulated process of cell proliferation, migration, and differentiation. The use of modern developmental biological and genetic approaches has markedly enriched our understanding of the molecular and cellular mechanisms underlying these developmental events. Additionally, the application of similar approaches to study diverse vascular diseases has resulted in paradigm-shifting insights into pathogenesis. Further investigations into the biology of vascular cells in development and disease promise to have major ramifications on therapeutic strategies to combat pathologies of the vasculature.

      PubDate: 2016-10-16T11:15:45Z
      DOI: 10.1016/bs.apha.2016.08.001
  • Smooth Muscle Phenotypic Diversity: Effect on Vascular Function and Drug
    • Authors: S.A. Fisher
      Abstract: Publication date: Available online 14 October 2016
      Source:Advances in Pharmacology
      Author(s): S.A. Fisher
      At its simplest resistance to blood flow is regulated by changes in the state of contraction of the vascular smooth muscle (VSM), a function of the competing activities of the myosin kinase and phosphatase determining the phosphorylation and activity of the myosin ATPase motor protein. In contrast, the vascular system of humans and other mammals is incredibly complex and highly regulated. Much of this complexity derives from phenotypic diversity within the smooth muscle, reflected in very differing power outputs and responses to signaling pathways that regulate vessel tone, presumably having evolved over the millennia to optimize vascular function and its control. The highly regulated nature of VSM tone, described as pharmacomechanical coupling, likely underlies the many classes of drugs in clinical use to alter vascular tone through activation or inhibition of these signaling pathways. This review will first describe the phenotypic diversity within VSM, followed by presentation of specific examples of how molecular diversity in signaling, myofilament, and calcium cycling proteins impacts arterial smooth muscle function and drug responses.

      PubDate: 2016-10-16T11:15:45Z
      DOI: 10.1016/bs.apha.2016.07.003
  • Calcium Channels in Vascular Smooth Muscle
    • Authors: D. Ghosh; A.U. Syed; M.P. Prada; M.A. Nystoriak; L.F. Santana; M. Nieves-Cintrón; M.F. Navedo
      Abstract: Publication date: Available online 14 October 2016
      Source:Advances in Pharmacology
      Author(s): D. Ghosh, A.U. Syed, M.P. Prada, M.A. Nystoriak, L.F. Santana, M. Nieves-Cintrón, M.F. Navedo
      Calcium (Ca2+) plays a central role in excitation, contraction, transcription, and proliferation of vascular smooth muscle cells (VSMs). Precise regulation of intracellular Ca2+ concentration ([Ca2+]i) is crucial for proper physiological VSM function. Studies over the last several decades have revealed that VSMs express a variety of Ca2+-permeable channels that orchestrate a dynamic, yet finely tuned regulation of [Ca2+]i. In this review, we discuss the major Ca2+-permeable channels expressed in VSM and their contribution to vascular physiology and pathology.

      PubDate: 2016-10-16T11:15:45Z
      DOI: 10.1016/bs.apha.2016.08.002
  • Ca2+/Calmodulin-Dependent Protein Kinase II in Vascular Smooth Muscle
    • Authors: F.Z. Saddouk; R. Ginnan; H.A. Singer
      Abstract: Publication date: Available online 14 October 2016
      Source:Advances in Pharmacology
      Author(s): F.Z. Saddouk, R. Ginnan, H.A. Singer
      Ca2+-dependent signaling pathways are central regulators of differentiated vascular smooth muscle (VSM) contractile function. In addition, Ca2+ signals regulate VSM gene transcription, proliferation, and migration of dedifferentiated or “synthetic” phenotype VSM cells. Synthetic phenotype VSM growth and hyperplasia are hallmarks of pervasive vascular diseases including hypertension, atherosclerosis, postangioplasty/in-stent restenosis, and vein graft failure. The serine/threonine protein kinase Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous mediator of intracellular Ca2+ signals. Its multifunctional nature, structural complexity, diversity of isoforms, and splice variants all characterize this protein kinase and make study of its activity and function challenging. The kinase has unique autoregulatory mechanisms, and emerging studies suggest that it can function to integrate Ca2+ and reactive oxygen/nitrogen species signaling. Differentiated VSM expresses primarily CaMKIIγ and -δ isoforms. CaMKIIγ isoform expression correlates closely with the differentiated phenotype, and some studies link its function to regulation of contractile activity and Ca2+ homeostasis. Conversely, synthetic phenotype VSM cells primarily express CaMKIIδ and substantial evidence links it to regulation of gene transcription, proliferation, and migration of VSM in vitro, and vascular hypertrophic and hyperplastic remodeling in vivo. CaMKIIδ and -γ isoforms have opposing functions at the level of cell cycle regulation, proliferation, and VSM hyperplasia in vivo. Isoform switching following vascular injury is a key step in promoting vascular remodeling. Recent availability of genetically engineered mice with smooth muscle deletion of specific isoforms and transgenics expressing an endogenous inhibitor protein (CAMK2N) has enabled a better understanding of CaMKII function in VSM and should facilitate future studies.

      PubDate: 2016-10-16T11:15:45Z
      DOI: 10.1016/bs.apha.2016.08.003
  • Notch Signaling in Vascular Smooth Muscle Cells
    • Authors: J.T. Baeten; B. Lilly
      Abstract: Publication date: Available online 26 August 2016
      Source:Advances in Pharmacology
      Author(s): J.T. Baeten, B. Lilly
      The Notch signaling pathway is a highly conserved pathway involved in cell fate determination in embryonic development and also functions in the regulation of physiological processes in several systems. It plays an especially important role in vascular development and physiology by influencing angiogenesis, vessel patterning, arterial/venous specification, and vascular smooth muscle biology. Aberrant or dysregulated Notch signaling is the cause of or a contributing factor to many vascular disorders, including inherited vascular diseases, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, associated with degeneration of the smooth muscle layer in cerebral arteries. Like most signaling pathways, the Notch signaling axis is influenced by complex interactions with mediators of other signaling pathways. This complexity is also compounded by different members of the Notch family having both overlapping and unique functions. Thus, it is vital to fully understand the roles and interactions of each Notch family member in order to effectively and specifically target their exact contributions to vascular disease. In this chapter, we will review the Notch signaling pathway in vascular smooth muscle cells as it relates to vascular development and human disease.

      PubDate: 2016-08-31T12:34:10Z
      DOI: 10.1016/bs.apha.2016.07.002
  • Potassium Channels in Regulation of Vascular Smooth Muscle Contraction and
    • Authors: W.F. Jackson
      Abstract: Publication date: Available online 17 August 2016
      Source:Advances in Pharmacology
      Author(s): W.F. Jackson
      Potassium channels importantly contribute to the regulation of vascular smooth muscle (VSM) contraction and growth. They are the dominant ion conductance of the VSM cell membrane and importantly determine and regulate membrane potential. Membrane potential, in turn, regulates the open-state probability of voltage-gated Ca2+ channels (VGCC), Ca2+ influx through VGCC, intracellular Ca2+, and VSM contraction. Membrane potential also affects release of Ca2+ from internal stores and the Ca2+ sensitivity of the contractile machinery such that K+ channels participate in all aspects of regulation of VSM contraction. Potassium channels also regulate proliferation of VSM cells through membrane potential-dependent and membrane potential-independent mechanisms. VSM cells express multiple isoforms of at least five classes of K+ channels that contribute to the regulation of contraction and cell proliferation (growth). This review will examine the structure, expression, and function of large conductance, Ca2+-activated K+ (BKCa) channels, intermediate-conductance Ca2+-activated K+ (KCa3.1) channels, multiple isoforms of voltage-gated K+ (KV) channels, ATP-sensitive K+ (KATP) channels, and inward-rectifier K+ (KIR) channels in both contractile and proliferating VSM cells.

      PubDate: 2016-08-22T06:25:32Z
  • Protein Kinase C as Regulator of Vascular Smooth Muscle Function and
           Potential Target in Vascular Disorders
    • Authors: H.C. Ringvold; R.A. Khalil
      Abstract: Publication date: Available online 18 July 2016
      Source:Advances in Pharmacology
      Author(s): H.C. Ringvold, R.A. Khalil
      Vascular smooth muscle (VSM) plays an important role in maintaining vascular tone. In addition to Ca2+-dependent myosin light chain (MLC) phosphorylation, protein kinase C (PKC) is a major regulator of VSM function. PKC is a family of conventional Ca2+-dependent α, β, and γ, novel Ca2+-independent δ, ɛ, θ, and η, and atypical ξ, and ι/λ isoforms. Inactive PKC is mainly cytosolic, and upon activation it undergoes phosphorylation, maturation, and translocation to the surface membrane, the nucleus, endoplasmic reticulum, and other cell organelles; a process facilitated by scaffold proteins such as RACKs. Activated PKC phosphorylates different substrates including ion channels, pumps, and nuclear proteins. PKC also phosphorylates CPI-17 leading to inhibition of MLC phosphatase, increased MLC phosphorylation, and enhanced VSM contraction. PKC could also initiate a cascade of protein kinases leading to phosphorylation of the actin-binding proteins calponin and caldesmon, increased actin–myosin interaction, and VSM contraction. Increased PKC activity has been associated with vascular disorders including ischemia–reperfusion injury, coronary artery disease, hypertension, and diabetic vasculopathy. PKC inhibitors could test the role of PKC in different systems and could reduce PKC hyperactivity in vascular disorders. First-generation PKC inhibitors such as staurosporine and chelerythrine are not very specific. Isoform-specific PKC inhibitors such as ruboxistaurin have been tested in clinical trials. Target delivery of PKC pseudosubstrate inhibitory peptides and PKC siRNA may be useful in localized vascular disease. Further studies of PKC and its role in VSM should help design isoform-specific PKC modulators that are experimentally potent and clinically safe to target PKC in vascular disease.

      PubDate: 2016-07-27T21:39:05Z
      DOI: 10.1016/bs.apha.2016.06.002
  • Sodium–Calcium Exchanger in Pig Coronary Artery
    • Authors: A.K. Grover
      Abstract: Publication date: Available online 15 July 2016
      Source:Advances in Pharmacology
      Author(s): A.K. Grover
      This review focuses on the sodium–calcium exchangers (NCX) in the left anterior descending coronary artery smooth muscle. Bathing tissues in Na+-substituted solutions caused them to contract. In cultured smooth muscle cells, it increased the cytosolic Ca2+ concentration and extracellular entry of 45Ca2+. All three activities were attributed to NCX since they were inhibited by NCX inhibitors. The tissues also expressed the sarco/endoplasmic reticulum (SER) Ca2+ pump SERCA2b whose activity was much greater than that of NCX. Inhibiting SERCA2b with thapsigargin decreased the NCX-mediated 45Ca2+ accumulation by the cells. The decrease was not observed in cells loaded with the Ca2+-chelator BAPTA. The results are consistent with a limited diffusional space model with a proximity between NCX and SERCA2b. NCX molecules appear to be colocalized with the subsarcolemmal SERCA2b based on studies on membrane flotation experiments and microscopic fluorescence imaging of antibody-labeled cells. Thapsigargin inhibition of SERCA2b moved NCX even closer to SER. This provides a model for the NCX-mediated Ca2+ refilling of SER in the arterial smooth muscle. The model for the NCX-mediated refilling of the depleted SER proposed for smooth muscle did not apply to endothelium in which NCX levels were greater and SERCA levels were lower than in smooth muscle. The effect of thapsigargin on the NCX-mediated Ca2+ accumulation which was observed in smooth muscle was absent in the endothelium. We propose that the coupling between NCX and smooth muscle may be tissue dependent.

      PubDate: 2016-07-27T21:39:05Z
      DOI: 10.1016/bs.apha.2016.06.001
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