CaV2.3 channels
| Channel name | CaV2.3 |
| Description | Voltage-gated calcium channel α1 subunit |
| Other names | R-type, α1E; rbE-II (in rat)1; BII-1, BII-2 (in rabbit)2 |
| Molecular information | Human: 2251aa, L29384, 2270aa, L29385,3 chr0.1q25-q31, CACNA1E |
| Rat: 2222aa,1 GenBank accession no. L15453 | |
| Mouse: 2272aa, Q61290 | |
| Associated subunits | α2δ/β, possibly γ |
| Functional assays | Voltage-clamp, patch-clamp, calcium imaging, neurotransmitter release |
| Current | ICa,R |
| Conductance | Not established |
| Ion selectivity | Ba2+ ∼ Ca2+ (rat)4; Ba2+ > Ca2+ (human)3 |
| Activation | Va = +3.5 mV, τa = 1.3 ms at 0 mV (human α1E/α2δ/β1-3, 15 mM Ba2+ charge carrier in HEK293 cells)3 |
| Va = –29.1 mV, τa = 2.1 ms at –10 mV (rat α1E/α2δ/β1b, 4 mM Ba2+ charge carrier in Xenopus oocytes)1 | |
| Inactivation | Vh = –71 mV, τh = 74 ms at 0 mV (human α1E/α2δ/β1-3, 15 mM Ba2+ charge carrier in HEK293 cells)3; Vh = –78.1 mV, τh = 100 ms at –10 mV (rat α1E/α2δ/β1b, 4 mM Ba2+ charge carrier in Xenopus oocytes)1 |
| Activators | None |
| Gating modifiers | None |
| Blockers | SNX-482, Ni2+ (IC50 = 27 μM), Cd2+ (IC50 = 0.8 μM), mibefradil (IC50 = 0.4 μM),10 volatile anesthetics11 |
| Radioligands | None |
| Channel distribution | Neurons (cell bodies, dendrites, some presynaptic terminals), heart, testes, pituitary |
| Physiological functions | Neurotransmitter release, repetitive firing, long-term potentiation, post-tetanic potentiation, neurosecretion12,13,14 |
| Mutations and pathophysiology | No point mutations in the native Cav2.3 gene have been reported; mice deficient for the Cav2.3 gene retain a substantial cerebellar R-type current,5 suggesting that R-type currents actually reflect a heterogeneous mixture of channels; homozygous Cav2.3-null mice survive to adulthood, reproduce, and are apparently behaviorally normal5,6; mutant mice exhibit an increased resistance to formalin-induced pain, suggesting an involvement of the Cav2.3 calcium channel in transmitting and/or the development of somatic inflammatory pain6 |
| Pharmacological significance | See “Comments” |
| Comments | Cav2.3 has been variously reported to encode a novel type of calcium channel with properties shared between both low- and high-threshold calcium channels1,4 or a type of high-threshold channel resistant to DHPs, ω-agatoxin-IVA, and ω-conotoxin-GVIA and called R-type (for “residual”)7 |
| The tarantula toxin SNX-482 blocks exogenously expressed Cav2.3 currents8 but is only partially effective on native cerebellar R-type currents,9 suggesting that Cav2.3 does not always conduct a significant portion of the R-type current as originally defined7; identified regions of alternative splicing include the domain II-III linker and carboxyl terminus and have been shown to affect channel kinetics and Ca2+-dependent stimulation1,2,3,15,16 |
aa, amino acids; chr., chromosome; HEK, human embryonic kidney; DHP, dihydropyridine.
↵1. Soong TW, Stea A, Hodson CD, Dubel SJ, Vincent SR, and Snutch TP (1993) Structure and functional expression of a member of the low voltage-activated calcium channel family. Science 260:1133-1136
↵2. Niidome T, Kim MS, Friedrich T, and Mori Y (1992) Molecular cloning and characterization of a novel calcium channel from rabbit brain. FEBS Lett 308:7-13
↵3. Williams ME, Marubio LM, Deal CR, Hans M, Brust PF, Philipson LH, Miller RJ, Johnson EC, Harpold MM, and Ellis SB (1994) Structure and functional characterization of neuronal α1E calcium channel subtypes. J Biol Chem 269:22347-22357
↵4. Bourinet E, Zamponi GW, Stea A, Soong TW, Lewis BA, Jones LP, Yue DT, and Snutch TP(1996) The α1E calcium channel exhibits permeation properties similar to low-voltage-activated calcium channels. J Neurosci, 16:4983-4993
↵5. Wilson SM, Toth PT, Oh SB, Gillard SE, Volsen S, Ren D, Philipson LH, Lee EC, Fletcher CF, Tessarollo L, et al. (2000) The status of voltage dependent calcium channels in α1E knockout mice. J Neurosci 20:8566-8571
↵6. Saegusa H, Kurhara T, Zong S, Minowa O, Kazuno A, Han W, Matsuda Y, Yamanaka H, Osanai M, Noda T, et al. (2000) Altered pain responses in mice lacking α1E subunit of the voltage dependent Ca channel. Proc Natl Acad Sci USA 97:6132-6137
↵7. Randall A and Tsien RW (1995) Pharmacological dissection of multiple types of calcium channel currents in rat cerebellar granule neurons. J Neurosci 15:2995-3012
↵8. Newcombe R, Szoke B, Palma A, Wang G, Chen XH, Hopkins W, Cong R, Miller J, Urge L, Tarczy-Hornoch K, et al. (1998) Selective peptide antagonist of the class E calcium channel from the venom of the tarantula Hysterocrates gigas. Biochemistry 37:15353-15362
↵9. Tottene A, Volsen S, and Pietrobon D (2000) α1E subunits form the pore of three cerebellar R-type calcium channels with different pharmacological and permeation properties. J Neurosci 20:171-178
↵10. 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
↵11. Kamatchi GL, Chan CK, Snutch T, Durieux ME, and Lynch III C (1999) Volatile anesthetic inhibition of neuronal Ca channel currents expressed in Xenopus oocytes. Brain Res 831:85-96
↵12. Dietrich D, Kirschstein T, Kukley M, Pereverzev A, von der Brelie C, Schneider T, and Beck H (2003) Functional specialization of presynaptic Cav2.3 Ca2+ channels. Neuron 39:483-496
↵13. Jing X, Li DQ, Olofsson CS, Salehi A, Surve VV, Caballero J, Ivarsson R, Lundquist I, Pereverzev A, Schneider T, et al. (2005) CaV2.3 calcium channels control second-phase insulin release. J Clin Investig 115:146-154
↵14. Pereverzev A, Salehi A, Mikhna M, Renstrom E, Hescheler J, Weiergraber M, Smyth N, and Schneider T (2005) The ablation of the Cav2.3/E-type voltage-gated Ca2+ channel causes a mild phenotype despite an altered glucose induced glucagon response in isolated islets of Langerhans. Eur J Pharmacol 511:65-72
↵15. Pereverzev A, Leroy J, Krieger A, Malecot CO, Hescheler J, Pfitzer G, Klockner U, and Schneider T (2002) Alternate splicing in the cytosolic II-III loop and the carboxy terminus of human E-type voltage-gated Ca2+ channels: electrophysiological characterization of isoforms. Mol Cell Neurosci 21:352-365
↵16. Klocker U, Pereverzev A, Leroy J, Krieger A, Vajna R, Pfitzer G, Hescheler J, Malecot CO, and Schneider T (2004) The cytoplasmic loop of Cav2.3 provides an essential determinant for the phorbol ester-mediated stimulation of E-type Ca2+ channel activity. Eur J Neurosci 19:2659-2668