Overview: Calcium (Ca2+) channels are voltage-gated ion channels present in the membrane of most excitable cells. The nomenclature for Ca2+ channels was proposed by Ertel et al. (2000) and approved by the NC-IUPHAR subcommittee on Ca2+ channels (Catterall et al., 2005). Ca2+ channels form hetero-oligomeric complexes. The α1 subunit is pore-forming and provides the extracellular binding site(s) for practically all agonists and antagonists. The 10 cloned α subunits can be grouped into three families: (i) the high voltage-activated dihydropyridine-sensitive (L-type, CaV1.x) channels; (ii) the high voltage-activated dihydropyridine-insensitive (CaV2.x) channels; and (iii) the low voltage-activated (T-type, CaV3.x) channels. Each α1 subunit has four homologous repeats (I–IV), each repeat having six transmembrane domains and a pore-forming region between transmembrane domains S5 and S6. Gating is thought to be associated with the membrane-spanning S4 segment, which contains highly conserved positive charges. Many of the α1 subunit genes give rise to alternatively spliced products. At least for high voltage-activated channels, it is likely that native channels comprise co-assemblies of α1, β and α2–δ subunits. The γ subunits have not been proven to associate with channels other than α1s. The α2–δ1 and α2–δ2 subunits bind gabapentin and pregabalin.
| Nomenclature | CaV1.1 | CaV1.2 | CaV1.3 | CaV1.4 | CaV2.1 |
|---|---|---|---|---|---|
| Alternative names | L-type, α1S, skeletal muscle L | L-type, α1C, cardiac or smooth muscle L | L-type, α1D | L-type, α1F | P-type, Q-type, α1a |
| Ensembl ID | ENSG00000081248 | ENSG00000151067 | ENSG00000157388 | ENSG00000102001 | ENSG00000141837 |
| Activators | (-)-(S)-BayK8644 SZ(+)-(S)-202-791 FPL64176 | (-)-(S)-BayK8644 SZ(+)-(S)-202-791 FPL64176 | (-)-(S)-BayK8644 | (-)-(S)-BayK8644 | |
| Blockers | Dihydropyridine antagonists, for example nifedipine, diltiazem, verapamil, calciseptine | Dihydropyridine antagonists, for example nifedipine, diltiazem, verapamil, calciseptine | Less sensitive to dihydropyridine antagonists verapamil | Less sensitive to dihydropyridine antagonists | ω-Agatoxin IVA (P: IC50∼ 1 nM) (Q: IC50∼ 90 nM) ω-Agatoxin IVB, ω-Conotoxin, MVIIC |
| Functional characteristics | High voltage-activated, slow inactivation | High voltage-activated, slow inactivation (Ca2+-dependent) | Low–moderate voltage-activated, slow inactivation (Ca2+-dependent) | Moderate voltage-activated, slow inactivation (Ca2+-independent) | Moderate voltage-activated, moderate inactivation |
| Nomenclature | CaV2.2 | CaV2.3 | CaV3.1 | CaV3.2 | CaV3.3 |
|---|---|---|---|---|---|
| Alternative names | N-type, α1B | R-type, α1E | T-type, α1G | T-type, α1H | T-type, α1I |
| Ensembl ID | ENSG00000148408 | ENSG00000198216 | ENSG00000006283 | ENSG00000196557 | ENSG00000100346 |
| Blockers | ω-Conotoxin GVIA, ω-Conotoxin MVIIC | SNX482 (may not be completely specific), high Ni2+ | Mibefradil, low sensitivity to Ni2+, kurtoxin, SB-209712 | Mibefradil, high sensitivity to Ni2+, kurtoxin, SB-209712 | Mibefradil, low sensitivity to Ni2+, kurtoxin, SB-209712 |
| Functional characteristics | High voltage-activated, moderate inactivation | Moderate voltage-activated, fast inactivation | Low voltage-activated, fast inactivation | Low voltage-activated, fast inactivation | Low voltage-activated, moderate inactivation |
In many cell types, P and Q current components cannot be adequately separated, and many researchers in the field have adopted the terminology ‘P/Q-type’ current when referring to either component. Ziconotide (a synthetic peptide equivalent to ω-conotoxin) has been approved for the treatment of chronic pain (Williams et al., 2008).
Glossary
Abbreviations:
- (-)-(S)-SNX482
41 amino acid peptide-(GVDKAGCRYMFGGCSVNDDCCPRLGCHSLFSYCAWDLTFSD)
- (-)-(S)-BAYK8664
methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluromethylphenyl)-pyridine-5-carboxylate
- FPL64176
2,5-dimethyl-4-[2(phenylmethyl)benzoyl]-H-pyrrole-3-carboxylate
- SB-209712
(1,6,bis{1-[4-(3-phenylpropyl)piperidinyl]}hexane)
- SZ(+)-(S)-202-791
isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylate
Further Reading
Belardetti F, Zamponi GW (2008). Linking calcium-channel isoforms to potential therapies. Curr Opin Investig Drugs9: 707–715.
Catterall WA (2000). Structure and regulation of voltage-gated Ca2+ channels. Ann Rev Cell Dev Biol16: 521–555.
Catterall WA, Perez-Reyes E, Snutch TP, Striessing J (2005). International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol Rev57: 411–425.
Catterall WA, Dib-Hajj S, Meisler MH, Pietrobon D (2008). Inherited neuronal ion channelopathies: new windows on complex neurological diseases. J Neurosci28: 11768–11777.
Davies A, Hendrich J, Van Minh AT, Wratten J, Douglas L, Dolphin AC (2007). Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels. Trends Pharmacol Sci28: 220–228.
Dolphin AC (2003). G protein modulation of voltage-gated calcium channels. Pharmacol Rev55: 607–627.
Elmslie KS (2004). Calcium channel blockers in the treatment of disease. J Neurosci Res75: 733–741.
Ertel EA, Campbell KP, Harpold MM, Hofmann F, Mori Y, Perez-Reyes E et al. (2000). Nomenclature of voltage-gated calcium channels. Neuron25: 533–535.
Han TS, Teichert RW, Olivera BM, Bulaj G (2008). Conus venoms – a rich source of peptide-based therapeutics. Curr Pharm Des14: 2462–2479.
Hofmann F, Lacinova L, Klugbauer N (1999). Voltage-dependent calcium channels; from structure to function. Rev Physiol Biochem Pharmacol139: 35–87.
Kochegarov AA (2003). Pharmacological modulators of voltage-gated calcium channels and their therapeutic application. Cell Calcium33: 145–162.
Lewis RJ, Garcia ML (2003). Therapeutic potential of venom peptides. Nat Rev Drug Discov2: 790–802.
Lory P, Chemin J (2007). Towards the discovery of novel T-type calcium channel blockers. Expert Opin Ther Targets11: 717–722.
Nelson MT, Todorovic SM, Perez-Reyes E (2006). The role of T-type calcium channels in epilepsy and pain. Curr Pharm Des12: 2189–2197.
Perez-Reyes E (2003). Molecular physiology of low-voltage-activated T-type calcium channels. Physiol Rev83: 117–161.
Taylor CP, Anelotti T, Fauman E (2007). Pharmacology and mechanism of action of pregabalin; the calcium channel alpha2-delta subunit as a target for antiepileptic drug discovery. Epilepsy Res73: 137–150.
Terlau H, Olivera BM (2004). Conus venoms: a rich source of novel ion channel-targeted peptides. Physiol Rev84: 41–68.
Triggle DJ (2006). L-type calcium channels. Curr Pharm Des12: 443–457.
Triggle DJ (2007). Calcium channel antagonists: clinical uses – past, present and future. Biochem Pharmacol74: 1–9.
Trimmer JS, Rhodes KJ (2004). Localisation of voltage-gated ion channels in mammalian brain. Ann Rev Physiol66: 477–519.
Williams JA, Day M, Heavner JE (2008). Ziconotide: an update and review. Expert Opin Pharmacother9: 1575–1583.
Yamamoto T, Takahara A (2009). Recent updates of N-type calcium channel blockers with therapeutic potential for neuropathic pain and stroke. Curr Top Med Chem9: 377–395.
Yu FH, Catterall WA (2004). The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE2004 (253): re15.
Zamponi GW, Lewis RJ, Todorovic SM, Arneric SP, Snutch TP. (2009). Role of voltage-gated calcium channels in ascending pain pathways. Brain Res Rev60: 84–89.