Figure 1. Subunit architecture of calcium channels. Left. The subunit architecture of the skeletal muscle CaV1.1 channel is depicted as described in original biochemical studies [51]. P, protein phosphorylation. Curvy lines, glycosylation. Right. The subunit architecture of the skeletal muscle CaV1.1 channel is depicted as revealed in cryo-electron microscopy studies [59]. The different subdomains of the α2δ-1 subunit are shown in different colors: Von Willebrand Factor domain (green), Cache domain 1 (brown), and Cache domain 2 (purple). CTD, C-terminal domain.
Figure 2. Structure of calcium channels. A. A transmembrane folding diagram of the voltage-gated calcium channel α11.1 subunit. Transmembrane segments S1-S4 form the voltage-sensing module. The S4 segments with their positive gating charges are highlighted in yellow. Transmembrane segments S5 and S6 and the P loop between them are highlighted in green. B. Structural basis for selective calcium conductance. Left. Superimposed high-resolution images of the ion selectivity filters of the bacterial sodium channel NaVAb and its Ca2+-selective derivative CaVAb. Native amino acid residues of NaVAb are in black; substituted amino acid residues in CaVAb are in red. Right. High-resolution structure of the calcium selectivity filter in CaVAb [53]. Amino acid residues of T1775 to D181 in stick representation. Green, calcium ions with electron density illustrated in mesh. Red, ordered water molecules.
|
* Here we list only the primary localisations and the standard antagonists most widely used in research. Much more detail is given in the Ion Channel Database.
The complete amino acid sequences of these α1 subunits are more than 70% identical within a subfamily but less than 40% identical among the three subfamilies. These family relationships are illustrated for the conserved transmembrane and pore domains in Figure 3. Division of Ca2+ channels into these three families is phylogenetically ancient, as one representative of each is found in the C. elegans genome. Consequently, the genes for the different α1 subunits have become widely dispersed in the genome and even the most closely related members of the family are not clustered on single chromosomes in mammals.
Figure 3. Sequence similarity of voltage-gated calcium channel α1 subunits. Comparison of the amino acid sequence similarity of mammalian calcium channels. Only the membrane-spanning regions and pore loops are compared. All sequence pairs were aligned and compared, which led to the clear separation of the three subfamilies (CaV1, CaV2, CaV3) that have internal sequence identity of >80%. Consensus sequences were defined for all three families and compared to one another, yielding inter-family sequence identity of 52% (CaV1 vs. CaV2) and 28% (CaV3 vs. CaV1 or CaV2).
Figure 4. Structure of the drug receptor sites in voltage-gated Ca2+ channels. Left: Top. Top view of the model Ca2+ channel CavAb. Voltage-sensing domains in blue; pore domain in gray. Ca2+ is bound in the central pore (red), and amlodipine is bound to its receptor site on the outer surface of the pore domain. Bottom. Side view. A cross section of CavAb with verapamil bound in the central Cavity in the pore, just below the ion selectivity filter. Right: The position of the pore domain-forming S5 and S6 helices within the rabbit Cav1.1 channel complex (rCav1.1) is shown on the left. The insets show the interaction sites for various Ca2+-channel blockers nifedipine, verapamil and diltiazem as well as the Ca2+-channel activator BAY K 8644 (from Wu et al., 2019, [63]).
1. Baig SM, Koschak A, Lieb A, Gebhart M, Dafinger C, Nürnberg G, Ali A, Ahmad I, Sinnegger-Brauns MJ, Brandt N et al.. (2011) Loss of Ca(v)1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness. Nat Neurosci, 14 (1): 77-84. [PMID:21131953]
2. Bech-Hansen NT, Naylor MJ, Maybaum TA, Pearce WG, Koop B, Fishman GA, Mets M, Musarella MA, Boycott KM. (1998) Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness. Nat Genet, 19 (3): 264-7. [PMID:9662400]
3. Birnbaumer L, Campbell KP, Catterall WA, Harpold MM, Hofmann F, Horne WA, Mori Y, Schwartz A, Snutch TP, Tanabe T et al.. (1994) The naming of voltage-gated calcium channels. Neuron, 13 (3): 505-6. [PMID:7917287]
4. Buraei Z, Yang J. (2015) Inhibition of Voltage-Gated Calcium Channels by RGK Proteins. Curr Mol Pharmacol, 8 (2): 180-7. [PMID:25966691]
5. Campiglio M, Costé de Bagneaux P, Ortner NJ, Tuluc P, Van Petegem F, Flucher BE. (2018) STAC proteins associate to the IQ domain of CaV1.2 and inhibit calcium-dependent inactivation. Proc Natl Acad Sci U S A, 115 (6): 1376-1381. [PMID:29363593]
6. Carbone E, Lux HD. (1984) A low voltage-activated, fully inactivating Ca channel in vertebrate sensory neurones. Nature, 310 (5977): 501-2. [PMID:6087159]
7. Catterall WA. (2000) Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol, 16: 521-55. [PMID:11031246]
8. Catterall WA. (2011) Voltage-gated calcium channels. Cold Spring Harb Perspect Biol, 3 (8): a003947. [PMID:21746798]
9. Catterall WA. (2015) Regulation of Cardiac Calcium Channels in the Fight-or-Flight Response. Curr Mol Pharmacol, 8 (1): 12-21. [PMID:25966697]
10. Chandy KG, Gutman GA. (1993) Nomenclature for mammalian potassium channel genes. Trends Pharmacol Sci, 14 (12): 434. [PMID:8122319]
11. Chemin J, Siquier-Pernet K, Nicouleau M, Barcia G, Ahmad A, Medina-Cano D, Hanein S, Altin N, Hubert L, Bole-Feysot C et al.. (2018) De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene. Brain, 141 (7): 1998-2013. [PMID:29878067]
12. Choe W, Messinger RB, Leach E, Eckle VS, Obradovic A, Salajegheh R, Jevtovic-Todorovic V, Todorovic SM. (2011) TTA-P2 is a potent and selective blocker of T-type calcium channels in rat sensory neurons and a novel antinociceptive agent. Mol Pharmacol, 80 (5): 900-10. [PMID:21821734]
13. Ertel EA, Campbell KP, Harpold MM, Hofmann F, Mori Y, Perez-Reyes E, Schwartz A, Snutch TP, Tanabe T, Birnbaumer L, Tsien RW, Catterall WA. (2000) Nomenclature of voltage-gated calcium channels. Neuron, 25 (3): 533-5. [PMID:10774722]
14. Ferron L, Kadurin I, Dolphin AC. (2018) Proteolytic maturation of α2δ controls the probability of synaptic vesicular release. Elife, 7. DOI: 10.7554/eLife.37507 [PMID:29916807]
15. Flucher BE. (2020) Skeletal muscle CaV1.1 channelopathies. Pflugers Arch, 472 (7): 739-754. [PMID:32222817]
16. Flucher BE, Campiglio M. (2019) STAC proteins: The missing link in skeletal muscle EC coupling and new regulators of calcium channel function. Biochim Biophys Acta Mol Cell Res, 1866 (7): 1101-1110. [PMID:30543836]
17. Gebhart M, Juhasz-Vedres G, Zuccotti A, Brandt N, Engel J, Trockenbacher A, Kaur G, Obermair GJ, Knipper M, Koschak A et al.. (2010) Modulation of Cav1.3 Ca2+ channel gating by Rab3 interacting molecule. Mol Cell Neurosci, 44 (3): 246-59. [PMID:20363327]
18. Glossmann H, Striessnig J. (1990) Molecular properties of calcium channels. Rev Physiol Biochem Pharmacol, 114: 1-105. [PMID:2155469]
19. Hall DD, Dai S, Tseng PY, Malik Z, Nguyen M, Matt L, Schnizler K, Shephard A, Mohapatra DP, Tsuruta F et al.. (2013) Competition between α-actinin and Ca²⁺-calmodulin controls surface retention of the L-type Ca²⁺ channel Ca(V)1.2. Neuron, 78 (3): 483-97. [PMID:23664615]
20. Han Y, Kaeser PS, Südhof TC, Schneggenburger R. (2011) RIM determines Ca²+ channel density and vesicle docking at the presynaptic active zone. Neuron, 69 (2): 304-16. [PMID:21262468]
21. Heinemann SH, Terlau H, Stühmer W, Imoto K, Numa S. (1992) Calcium channel characteristics conferred on the sodium channel by single mutations. Nature, 356 (6368): 441-3. [PMID:1313551]
22. Helbig KL, Lauerer RJ, Bahr JC, Souza IA, Myers CT, Uysal B, Schwarz N, Gandini MA, Huang S, Keren B et al.. (2018) De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. Am J Hum Genet, 103 (5): 666-678. [PMID:30343943]
23. Hockerman GH, Peterson BZ, Johnson BD, Catterall WA. (1997) Molecular determinants of drug binding and action on L-type calcium channels. Annu Rev Pharmacol Toxicol, 37: 361-96. [PMID:9131258]
24. Hofmann F, Lacinová L, Klugbauer N. (1999) Voltage-dependent calcium channels: from structure to function. Rev Physiol Biochem Pharmacol, 139: 33-87. [PMID:10453692]
25. Horstick EJ, Linsley JW, Dowling JJ, Hauser MA, McDonald KK, Ashley-Koch A, Saint-Amant L, Satish A, Cui WW, Zhou W et al.. (2013) Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy. Nat Commun, 4: 1952. [PMID:23736855]
26. Kaeser PS, Deng L, Wang Y, Dulubova I, Liu X, Rizo J, Südhof TC. (2011) RIM proteins tether Ca2+ channels to presynaptic active zones via a direct PDZ-domain interaction. Cell, 144 (2): 282-95. [PMID:21241895]
27. Kiyonaka S, Wakamori M, Miki T, Uriu Y, Nonaka M, Bito H, Beedle AM, Mori E, Hara Y, De Waard M et al.. (2007) RIM1 confers sustained activity and neurotransmitter vesicle anchoring to presynaptic Ca2+ channels. Nat Neurosci, 10 (6): 691-701. [PMID:17496890]
28. Liu G, Papa A, Katchman AN, Zakharov SI, Roybal D, Hennessey JA, Kushner J, Yang L, Chen BX, Kushnir A et al.. (2020) Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics. Nature, 577 (7792): 695-700. [PMID:31969708]
29. Llinás R, Sugimori M, Hillman DE, Cherksey B. (1992) Distribution and functional significance of the P-type, voltage-dependent Ca2+ channels in the mammalian central nervous system. Trends Neurosci, 15 (9): 351-5. [PMID:1382335]
30. Marcantoni A, Calorio C, Hidisoglu E, Chiantia G, Carbone E. (2020) Cav1.2 channelopathies causing autism: new hallmarks on Timothy syndrome. Pflugers Arch, 472 (7): 775-789. [PMID:32621084]
31. Nanou E, Catterall WA. (2018) Calcium Channels, Synaptic Plasticity, and Neuropsychiatric Disease. Neuron, 98 (3): 466-481. [PMID:29723500]
32. Nowycky MC, Fox AP, Tsien RW. (1985) Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature, 316 (6027): 440-3. [PMID:2410796]
33. Olivera BM, Miljanich GP, Ramachandran J, Adams ME. (1994) Calcium channel diversity and neurotransmitter release: the omega-conotoxins and omega-agatoxins. Annu Rev Biochem, 63: 823-67. [PMID:7979255]
34. Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M et al.. (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell, 87 (3): 543-52. [PMID:8898206]
35. Ortner NJ, Kaserer T, Copeland JN, Striessnig J. (2020) De novo CACNA1D Ca2+ channelopathies: clinical phenotypes and molecular mechanism. Pflugers Arch, 472 (7): 755-773. [PMID:32583268]
36. Ortner NJ, Pinggera A, Hofer NT, Siller A, Brandt N, Raffeiner A, Vilusic K, Lang I, Blum K, Obermair GJ et al.. (2020) RBP2 stabilizes slow Cav1.3 Ca2+ channel inactivation properties of cochlear inner hair cells. Pflugers Arch, 472 (1): 3-25. [PMID:31848688]
37. Perez-Reyes E. (2003) Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev, 83 (1): 117-61. [PMID:12506128]
38. Perez-Reyes E, Cribbs LL, Daud A, Lacerda AE, Barclay J, Williamson MP, Fox M, Rees M, Lee JH. (1998) Molecular characterization of a neuronal low-voltage-activated T-type calcium channel. Nature, 391 (6670): 896-900. [PMID:9495342]
39. Pietrobon D, Striessnig J. (2003) Neurobiology of migraine. Nat Rev Neurosci, 4 (5): 386-98. [PMID:12728266]
40. Polster A, Dittmer PJ, Perni S, Bichraoui H, Sather WA, Beam KG. (2018) Stac Proteins Suppress Ca2+-Dependent Inactivation of Neuronal l-type Ca2+ Channels. J Neurosci, 38 (43): 9215-9227. [PMID:30201773]
41. Polster A, Perni S, Bichraoui H, Beam KG. (2015) Stac adaptor proteins regulate trafficking and function of muscle and neuronal L-type Ca2+ channels. Proc Natl Acad Sci U S A, 112 (2): 602-6. [PMID:25548159]
42. Randall A, Tsien RW. (1995) Pharmacological dissection of multiple types of Ca2+ channel currents in rat cerebellar granule neurons. J Neurosci, 15 (4): 2995-3012. [PMID:7722641]
43. Reuter H. (1979) Properties of two inward membrane currents in the heart. Annu Rev Physiol, 41: 413-24. [PMID:373598]
44. Reuter H. (1983) Calcium channel modulation by neurotransmitters, enzymes and drugs. Nature, 301 (5901): 569-74. [PMID:6131381]
45. Scholl UI, Stölting G, Nelson-Williams C, Vichot AA, Choi M, Loring E, Prasad ML, Goh G, Carling T, Juhlin CC et al.. (2015) Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. Elife, 4: e06315. [PMID:25907736]
46. Snutch TP, Leonard JP, Gilbert MM, Lester HA, Davidson N. (1990) Rat brain expresses a heterogeneous family of calcium channels. Proc Natl Acad Sci USA, 87 (9): 3391-3395. [PMID:1692134]
47. Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, Sanguinetti MC, Keating MT. (2005) Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci USA, 102 (23): 8089-8096; discussion 8086-8088. [PMID:15863612]
48. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K et al.. (2004) Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell, 119 (1): 19-31. [PMID:15454078]
49. Striessnig J. (1999) Pharmacology, structure and function of cardiac L-type Ca(2+) channels. Cell Physiol Biochem, 9 (4-5): 242-69. [PMID:10575201]
50. Strom TM, Nyakatura G, Apfelstedt-Sylla E, Hellebrand H, Lorenz B, Weber BH, Wutz K, Gutwillinger N, Rüther K, Drescher B et al.. (1998) An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nat Genet, 19 (3): 260-3. [PMID:9662399]
51. Takahashi M, Seagar MJ, Jones JF, Reber BF, Catterall WA. (1987) Subunit structure of dihydropyridine-sensitive calcium channels from skeletal muscle. Proc Natl Acad Sci U S A, 84 (15): 5478-5482. [PMID:2440051]
52. Tang L, Gamal El-Din TM, Lenaeus MJ, Zheng N, Catterall WA. (2019) Structural Basis for Diltiazem Block of a Voltage-Gated Ca2+ Channel. Mol Pharmacol, 96 (4): 485-492. [PMID:31391290]
53. Tang L, Gamal El-Din TM, Payandeh J, Martinez GQ, Heard TM, Scheuer T, Zheng N, Catterall WA. (2014) Structural basis for Ca2+ selectivity of a voltage-gated calcium channel. Nature, 505 (7481): 56-61. [PMID:24270805]
54. Tang L, Gamal El-Din TM, Swanson TM, Pryde DC, Scheuer T, Zheng N, Catterall WA. (2016) Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs. Nature, 537 (7618): 117-121. [PMID:27556947]
55. Tsien RW, Lipscombe D, Madison D, Bley K, Fox A. (1995) Reflections on Ca(2+)-channel diversity, 1988-1994. Trends Neurosci, 18 (2): 52-4. [PMID:7537405]
56. Venance SL, Cannon SC, Fialho D, Fontaine B, Hanna MG, Ptacek LJ, Tristani-Firouzi M, Tawil R, Griggs RC, CINCH investigators. (2006) The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain, 129 (Pt 1): 8-17. [PMID:16195244]
57. Wang S, Cortes CJ. (2021) Interactions with PDZ proteins diversify voltage-gated calcium channel signaling. J Neurosci Res, 99 (1): 332-348. [PMID:32476168]
58. Wu J, Yan Z, Li Z, Qian X, Lu S, Dong M, Zhou Q, Yan N. (2016) Structure of the voltage-gated calcium channel Ca(v)1.1 at 3.6 Å resolution. Nature, 537 (7619): 191-196. [PMID:27580036]
59. Wu J, Yan Z, Li Z, Yan C, Lu S, Dong M, Yan N. (2015) Structure of the voltage-gated calcium channel Cav1.1 complex. Science, 350 (6267): aad2395. [PMID:26680202]
60. Yu FH, Catterall WA. (2004) The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE, 2004 (253): re15. [PMID:15467096]
61. Zamponi GW. (2016) Targeting voltage-gated calcium channels in neurological and psychiatric diseases. Nat Rev Drug Discov, 15 (1): 19-34. [PMID:26542451]
62. Zamponi GW, Striessnig J, Koschak A, Dolphin AC. (2015) The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential. Pharmacol Rev, 67 (4): 821-70. [PMID:26362469]
63. Zhao Y, Huang G, Wu J, Wu Q, Gao S, Yan Z, Lei J, Yan N. (2019) Molecular Basis for Ligand Modulation of a Mammalian Voltage-Gated Ca2+ Channel. Cell, 177 (6): 1495-1506.e12. [PMID:31150622]
64. Zhao Y, Huang G, Wu Q, Wu K, Li R, Lei J, Pan X, Yan N. (2019) Cryo-EM structures of apo and antagonist-bound human Cav3.1. Nature, 576 (7787): 492-497. [PMID:31766050]
65. Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC. (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet, 15 (1): 62-9. [PMID:8988170]