CaV2.1 channels

Channel name Cav2.1
Description Voltage-gated calcium channel α1 subunit
Other names α1A, P-type, Q-type, rbA-I (in rat)1; BI-1, BI-2 (in rabbit)2
Molecular information Human: 2510aa, AF004883, 2662aa, AF004884, chr. 19p13, CACNA1A
Rat: 2212aa, M64373
Mouse: 2165aa, NM007578, NP031604
Rabbit: 2273aa, X57476 (see “Comments”)
Associated subunits α2δ, β, possibly γ
Functional assays Voltage-clamp, patch-clamp, calcium imaging, neurotransmitter release
Current ICa,P, ICa,Q
Conductance 9, 14, 19pS (P-type, cerebellar Purkinje neurones)4; 16–17pS (for α1A2δ/β in Xenopus oocytes)2,5,6
Ion selectivity Ba2+ > Ca2+
Activation Va = –5 mV for native P-type, Va = –11 mV for native Q-type (with 5 mM Ba2+ charge carrier)7
Va = –4.1 mV for rat α1A-a2δ/β4
Va = +2.1 mV for rat α1A-b2δ/β4 (with 5 mM Ba2+ charge carrier)6
Va = +9.5 mV; τa = 2.2 ms at +10 mV for human α1A-12δ/β1b in HEK293 cells (with 15 mM Ba2+ charge carrier)3
Inactivation Vh = –17.2 mV for α1A-a2δ/β4; Vh = –1.6 mV for α1A-b2δ/β4 (with 5 mM Ba2+ charge carrier); Vh = –17 mV, τh = 690 ms at +10 mV human α1A-12δ/β1b in HEK293 cells (with 15 mM Ba2+ charge carrier)3; τh > 1 s at 0 mV native P-type (with 5 mM Ba2+ charge carrier)7 (see “Comments”)
Activators None
Gating modifiers ω-agatoxin IVA (P-type Kd = 1–3 nM8; Q-type Kd ∼ 100–200 nM5,9), ω-agatoxin IVB6
Blockers ω-conotoxin MVIIC8; other blockers include piperidines, substituted diphenylbutylpiperidines, piperazines, volatile anesthetics, gabapentin, mibefradil, and peptide toxins DW13.3 and ω-conotoxin SVIB21,22,23,24,25,26 (see “Comments”)
Radioligands [125I]ω-conotoxin MVIIC
Channel distribution Neurons (presynaptic terminals, dendrites, some cell bodies), heart, pancreas, pituitary
Physiological functions Neurotransmitter release in central neurons and neuromuscular junction; excitation-secretion coupling in pancreatic β-cells
Mutations and pathophysiology Missense mutations in IS4-IS5, IIS4-IIS6, IIIS4-IIIS6, and IVS4-IVS6 cause FHM27; a common feature among FHM mutations is an apparent gain-of-function phenotype as a result of a shift in V50act to more hyperpolarized potentials (an increased probability of opening at the single channel level)28,29; other effects include a decrease in maximal current density at the whole-cell level and alterations of synaptic transmission28,29,30,31; point mutations in IIS1, IIS6-IIIS2, IIIS5-IIIS6, and IVS1-IVS5 cause episodic ataxia type-2, a polyglutamine expansion in the carboxyl region causes spinocerebellar ataxia type-6, and mutation of IS5-IS6 and IVS6 causes episodic and progressive ataxia10,11,12,27
Pharmacological significance Peptide toxins that selectively inhibit Cav2.1 channel block a significant portion of neurotransmission in the mammalian CNS13; block of Cav2.1 channels inhibits the late-phase formalin response and inflammatory pain but has no significant effect on mechanical allodynia or thermal hyperalgesia14,15,16,17; mice lacking a functional Cav2.1 gene exhibit cerebellar atrophy, severe muscle spasms, and ataxia and usually die by 3 to 4 weeks postnatal18,19
Comments Rates of inactivation and Vh are differentially affected by coexpression with β1b, β2a, β3, or β4 subunits, as well as by alternative splicing of the α1A subunit; identified regions of alternative splicing include the domain I-II linker, domain II-III linker, IVS3-IVS4, and the carboxyl terminus1,2,6,32,33,34; whole-cell currents with P-type kinetics seem to be conducted by the α1A-b splice variant coexpressed with any of the β subunits or by the α1A-a splice variant coexpressed with the β2a subunit6,7,20; whole-cell currents with Q-type kinetics seem to be encoded by α1A-a coexpressed with any of the β1b, β3, or β4 subunits6,20; whole-cell currents with Q-type pharmacology seem to be encoded by α1A splice variants containing Asp Pro residues in the domain IV S3-S4 linker, whereas whole-cell currents with P-type pharmacology seem to be conducted by α1A splice variants missing Asp Pro residues in IV S3-S4 linker3,6; alternative splicing also alters current density, current-voltage relations, calcium/calmodulin-dependent facilitation, sensitivity to mibefradil, and binding to intracellular synaptic proteins such as Mint1, CASK, syntaxin, and SNAP-2526,32,36
  • aa, amino acids; chr., chromosome; HEK, human embryonic kidney; FHM, familial hemiplegic migraine; CNS, central nervous system.

  • 1. Starr TVB, Prystay W, and Snutch TP (1991) Primary structure of a calcium channel that is highly expressed in the rat cerebellum. Proc Natl Acad Sci USA 88:5621-5625

  • 2. Mori Y, Friedrich T, Kim MS, Mikami A, Nakai J, Ruth P, Bosse E, Hofmann F, Flockerzi V, Furuichi T, et al. (1991) Primary structure and functional expression from complementary DNA of a brain calcium channel. Nature (Lond) 350:398-402

  • 3. Hans M, Urrutia A, Deal C, Brust PF, Stauderman K, Ellis SB, Harpold M, Johnson EC, and Williams ME (1999) Structural elements in domain IV that influence biophysical and pharmacological properties of human α1A-containing high-voltage-activated calcium channels. Biophys J 76:1384-1400

  • 4. Llinas R, Sugimori M, Hillman DE, and Cherksey B (1992) Distribution and functional significance of the P-type voltage-dependent calcium channels in the mammalian central nervous system. Trends Neurosci 15:2995-3012

  • 5. Sather WA, Tanabe T, Zhang JF, Mori Y, Adams ME, and Tsien RW (1993) Distinctive biophysical and pharmacological properties of class A (BI) calcium channel α1 subunits. Neuron 11:291-303

  • 6. Bourinet E, Soong TW, Sutton K, Slaymaker S, Mathews E, Monteil A, Zamponi GW, Nargeot J, and Snutch TP (1999) Splicing of α1A subunit gene generates phenotypic variants of P- and Q-type calcium channels. Nat Neurosci 2:407-415

  • 7. Merlestein PG, Foehring RC, Tkatch T, Song WJ, Baranauskas G, and Surmeier JD (1999) Properties of Q-type calcium channels in neostriatal and cortical neurons are correlated with β subunit expression. J Biol Chem 19:7268-7277

  • 8. Mintz IM, Venema VJ, Swiderek K, Lee T, Bean BP, and Adams ME (1992) P-type calcium channels blocked by the spider toxin ω-Aga-IVA. Nature (Lond) 355:827-829

  • 9. Randall A and Tsien RW (1995) Pharmacological dissection of multiple types of calcium channel currents in rat cerebellar granule neurons. J Biol Chem 15:2995-3012

  • 10. Ducros A, Denier C, Joutel A, Vahedi K, Michel A, Darcel F, Madigand M, Guerouaou D, Tison F, Julien J, et al. (1999) Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia. Am J Hum Genet 64:89-98

  • 11. Kraus RL, Sinnegger MJ, Koschak A, Glossmann H, Stenirri S, Carrera P, and Striessnig J (2000) Three new familial hemiplegic migraine mutants affect P/Q-type calcium channel kinetics. J Biol Chem 275:9239-9243

  • 12. 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 calcium channel gene CACNL1A4. Cell 87:543-552

  • 13. Dunlap K, Luebke JI, and Turner TJ (1995) Exocytotic Ca2+ channels in mammalian central neurons. Trends Neurosci 18:89-98

  • 14. Chaplan SR, Pogrel JW, and Yaksh TL (1994) Role of voltage-dependent calcium channel subtypes in experimental tactile allodynia. J Pharmacol Exp Ther 269:1117-1123

  • 15. Malmberg AB and Yaksh TL (1994) Voltage-sensitive calcium channels in spinal nociceptive processing: blockade of N- and P-type channels inhibits formalin-induced nociception. J Biol Chem 14:4882-4890

  • 16. Sluka KA (1997) Blockade of calcium channels can prevent the onset of secondary hyperalgesia and allodynia induced by intradermal injection of capsaicin in rats. Pain 71:157-164

  • 17. Sluka KA (1998) Blockade of N- and P/Q-type calcium channels reduces the secondary heat hyperalgesia induced by acute inflammation. J Pharmacol Exp Ther 287:232-237

  • 18. Jun K, Piedras-Rentera E, Smith SM, Wheeler DB, Lee SB, Lee TG, Chin H, Adams ME, Scheller RH, Tsien RW, and Shin HS (2000) Ablation of P/Q type calcium channel currents, altered synaptic transmission and progressive ataxia in mice lacking the α1A subunit. Proc Natl Acad Sci USA 96:15245-15250

  • 19. Fletcher CF, Tottene A, Lennon VA, Wilson SM, Dubel SJ, Paylor R, Hosford DA, Tessarollo L, McEnery MW, Pietrobon D, et al. (2001) Dystonia and cerebellar atrophy in Cacnl4 null mice lacking P/Q calcium channel activity. FASEB J 15:1288-1290

  • 20. Stea A, Tomlinson WJ, Soong TW, Bourinet E, Dubel SJ, Vincent SR, and Snutch TP (1994) Localization and functional properties of a rat brain α1A calcium channel reflect similarities to neuronal Q- and P-type channels. Proc Natl Acad Sci USA 91:10567-10580

  • 21. Sah DW and Bean BP (1994) Inhibition of P-type and N-type calcium channels by dopamine receptor antagonists. Mol Pharmacol 45:84-92

  • 22. Sutton K. Siok C, Stea A, Zamponi G, Heck SD, Volkmann RA, Ahlijanian MK, and Snutch TP (1998) Inhibition of neuronal calcium channels by a novel peptide spider toxin, DW 13.3. Mol Pharmacol 54:407-418

  • 23. Oka M, Itoh Y, Wada M, Yamamoto A, and Fujita T (2003) Gabapentin blocks L-type and P/Q-type Ca2+ channels involved in depolarization-stimulated nitric oxide synthase activity in primary cultures of neurons from mouse cerebral cortex. Pharm Res 20:897-899

  • 24. Dooley DJ, Donovan CM, Meder WP, and Whetzel SZ (2002) Preferential action of gabapentin and pregabalin at P/Q-type voltage-sensitive calcium channels: inhibition of K+-evoked [3H]-norepinephrine release from rat neocortical slices. Synapse 45:171-190

  • 25. Kamatchi GL, Chan CK, Snutch T, Durieux, and Lynch III C (1999) Volatile anesthetic inhibition of neuronal Ca channel currents expressed in Xenopus oocytes. Brain Res 831:85-96

  • 26. Jimenez C, Bourinet E, Leuranguer V, Richard S, Snutch TP, and Nargeot J (2000) Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels. Neuropharmacology 39:1-10

  • 27. Lorenzon NM and Beam K (2005) Calcium channelopathies, in Voltage-Gated Calcium Channels (Zamponi G ed) pp 240–261, Kluwer Academic/Plenum Publishers

  • 28. Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, Fletcher C, and Pietrobon D (2002) Familial hemiplegic migraine mutations increase Ca2+ influx through single human Cav2.1 channels and decrease maximal Cav2.1 current density in neurons. Proc Natl Acad Sci USA. 99:13284-13289

  • 29. van den Maagdenberg AM, Pietrobon D, Pizzorusso T, Kaja S, Broos LA, Cesetti T, van de Ven RC, Tottene A, van der Kaa J, Plomp JJ, et al. (2004) A Cacna1a knock in migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41:701-710

  • 30. Cao YQ, Piedras-Renteria ES, Smith GB, Chen G, Harata NC, and Tsien RW (2004) Presynaptic Ca2+ channels compete for channel type-preferring slots in altered neurotransmission arising from Ca2+ channelopathy. Neuron 43:387-400

  • 31. Cao Y and Tsien R (2005) Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca2+ channel activity and inhibitory synaptic transmission. Proc Natl Acad Sci USA 102:2590-2595

  • 32. Soong TW, DeMaria CD, Alvania RS, Zweifel LS, Liang MC, Mittman S, Agnew W, and Yue DT (2002) Systematic identification of splice variants inhuman P/Q-type channel α12.1 subunits: implications for current density and Ca2+-dependentinactivation. J Neurosci 22:10142-10152

  • 33. Krovetz HS, Helton TD, Crews AL and Horne WA (2000) C-Terminal alternative splicing changes the gating properties of a human spinal cord calcium channel alpha 1A subunit. J Neurosci 20:7564-7570

  • 34. Chaudhuri D, Chang SY, DeMaria CD, Alvania RS, Soong TW, and Yue DT (2004) Alternative splicing as a molecular switch for Ca2+/calmodulin-dependent facilitation of P/Q-type Ca2+ channels. J Neurosci 24:6334-6342

  • 35. Rettig J, Sheng ZH, Kim DK, Hodson CD, Snutch TP, and Catterall WA (1996) Isoform-specific interaction of the α1A subunits of brain Ca2+ channels with the presynaptic proteins syntaxin and SNAP-25. Proc Natl Acad Sci USA 93:7363-7368

  • 36. Maximov A, Sudhof TC, and Bezprozvanny I (1999) Association of neuronal calcium channels with modular adaptor proteins. J Biol Chem 274:24453-24456