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The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

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The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential 1521-0081/67/4/821–870$25.00 http://dx.doi.org/10.1124/pr.114.009654 PHARMACOLOGICAL REVIEWS Pharmacol Rev 67:821–870, October 2015 Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: DAVID R. SIBLEY The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential Gerald W. Zamponi, Joerg Striessnig, Alexandra Koschak, and Annette C. Dolphin Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada (G.W.Z.); Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria (J.S., A.K.); and Department of Neuroscience, Physiology, and Pharmacology, Division of Biosciences, University College London, London, United Kingdom (A.C.D.) Abstract. ....................................................................................823 I. Introduction. ..............................................................................823 II. CaV1 Channel Family .......................................................................824 Downloaded from A. Genes Encoding CaV1 Pore-Forming a1 Subunits.........................................824 B. Physiology of CaV1 Channels ............................................................824 1. Physiologic Roles of CaV1 Calcium Channels ..........................................824 a. CaV1.1............................................................................825 b. CaV1.2 and CaV1.3................................................................825 at Open University Library on January 24, 2020 i. L-Type Ca2+ Channels in the Heart. ..........................................825 ii. L-Type Ca2+ Channels in the Brain ..........................................827 iii. L-Type Ca2+ Channels in Endocrine Cells....................................828 iv. L-Type Ca2+ Channels in Auditory and Vestibular Hair Cells . .............829 c. CaV1.4............................................................................829 2. CaV1 Family Splice Variants . ......................................................829 C. CaV1 Channel Pathophysiology ..........................................................830 1. CaV1.1...............................................................................830 a. Hypokalemic Periodic Paralysis . ................................................830 b. Malignant Hyperthermia ..........................................................830 2. CaV1.2...............................................................................831 a. Timothy Syndrome................................................................831 b. Neuropsychiatric Disease..........................................................831 3. CaV1.3...............................................................................832 a. Parkinson’s Disease . ............................................................832 b. Hearing and Cardiac Dysfunction . ................................................832 c. Neuropsychiatric Disease..........................................................832 4. CaV1.4...............................................................................832 a. Congenital Stationary Night Blindness Type 2.....................................832 D. Pharmacology of CaV1 Channels . ......................................................833 1. Molecular Pharmacology. ............................................................833 2. Clinical Pharmacology ................................................................833 3. L-Type Calcium Channels as Potential Targets for Other Indications ..................834 a. Parkinson’s Disease Neuroprotection ..............................................835 b. Neuropsychiatric Disease..........................................................835 This research was supported in part by the Wellcome Trust [Senior Investigator Award 098360/Z/12/Z], the Research Councils UK Medical Research Council [Grants G0801756 and G0901758 (to A.C.D.)], and the Austrian Research Fund [Grants FWF F44020 (to J.S.) and P26881 (to A.K.)]. Address correspondence to: Dr. Annette C. Dolphin, Division of Biosciences, Department of Neuroscience, Physiology, and Pharmacology, Andrew Huxley Building, University College London, Gower St., London, WC1E 6BT UK. E-mail: [email protected] dx.doi.org/10.1124/pr.114.009654. 821 822 Zamponi et al. c. Febrile Seizures. ..................................................................836 d. Cardiovascular Disease. ...........................................................836 4. Pharmacological Targeting of L-Type Calcium Channels in the Brain..................836 a. CaV1.3-Selective L-Type Calcium Channel Blockers . ...............................836 b. L-Type Channel Activators as Therapeutics. .....................................837 c. Peptide Toxins Inhibiting L-Type Calcium Channels ...............................837 5. Indirect Modulation of CaV1 Calcium Channels . .....................................837 a. cAMP-Dependent Protein Kinase (Protein Kinase A) ...............................837 b. Membrane Phospholipids..........................................................838 c. Receptor Tyrosine Kinases . ......................................................838 d. Protein Interactions with L-Type Calcium Channels ...............................838 e. Novel Modulatory Mechanisms ....................................................838 E. Conclusion ..............................................................................838 III. CaV2 Channel Family .......................................................................838 A. Genes, Gene Products, and Splice Variants...............................................838 B. Physiologic Roles of CaV2 Calcium Channels . ..........................................839 C. CaV2 Channel Pathophysiology ..........................................................840 D. Molecular Pharmacology of CaV2 Channels...............................................841 1. CaV2.1 and CaV2.3 Channels and Their Potential Roles as Targets for Therapeutics . 841 2. CaV2.2 Channels and Their Roles as Targets for Therapeutics.........................841 a. Direct CaV2.2 Channel Blockers . ................................................841 b. G Protein Inhibition of CaV2.2 Channels. ..........................................844 c. Inhibition of CaV2.2 Channel Trafficking ..........................................844 d. Interference with CaV2.2 Coupling to the Synaptic Vesicle Release Machinery ......845 E. Conclusion ..............................................................................845 IV. CaV3 Channel Family .......................................................................845 A. Genes, Gene Products, and Splice Variants...............................................845 B. Physiologic Roles of CaV3 Calcium Channels . ..........................................846 C. CaV3 Channel Pathophysiology ..........................................................846 D. Molecular Pharmacology of CaV3 Channels...............................................847 1. Inorganic Ions........................................................................847 2. Peptide Toxins .......................................................................848 3. Small Organic Molecules . ............................................................848 4. Interference with CaV3 Channel Regulation. ..........................................850 E. Conclusion ..............................................................................850 V. Auxiliary a2d and b Subunits ................................................................850 A. a2d Subunit Genes and Gene Products . ................................................851 1. a2d Subunit Splice Variants ..........................................................851 B. Physiologic Roles of a2d Proteins . ......................................................851 1. Roles in Calcium Channel Function. ................................................851 ABBREVIATIONS: ABT-639, 5-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl]-4-chloro-2-fluoro-N-(2-fluorophenyl) benzenesulfonamide; AID, a-interaction domain; APA, aldosterone-producing adenoma; ASD, autism spectrum disorder; AVN, atrioventric- ular node; BayK8644, 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid methyl ester; BPN-4689, Cp8, 1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-trione; CaM, calmodulin; CaMKII, calmodulin kinase II; CCB, Ca2+ channel blocker; CDI, Ca2+-dependent inactivation; CNS, central nervous system; CREB, cAMP/calcium response element binding protein; CTM, C-terminal modulatory structure; CSNB2, congenital stationary night blindness type 2; DCRD, distal C-terminal regulatory domain; DHP, dihydropyridine; DRG, dorsal root ganglion; DM, myotonic dystrophy; FHM, familial hemiplegic migraine; FPL 64167, 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]- 1H-pyrrole-3-carboxylic acid methyl ester; GIRK, G protein–coupled K+ channel; GPCR, G protein–coupled receptor; GWAS, genome-wide association study; HCN, hyperpolarization-activated cyclic nucleotide-gated channel; HypoPP, hypokalemic periodic paralysis; LTCC, L-type calcium channel; LTP, long-term potentiation; MH, malignant hyperthermia; miR, microRNA; NMP-7, (9-pentylcarbazol-3-yl)-piperidin-1- ylmethanone; NNC55-0396, (1S,2S)-2-[2-[[3-(1H-benzimidazol-2-yl)propyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-(1-methylethyl)-2-
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