Cav1.1 also known as thecalcium channel, voltage-dependent, L type, alpha 1S subunit, (CACNA1S), is aprotein which in humans is encoded by theCACNA1Sgene.[5] It is also known asCACNL1A3 and thedihydropyridine receptor (DHPR, so named due to the blocking action DHP has on it).
Cav1.1 is avoltage-dependent calcium channel found in thetransverse tubule of muscles. Inskeletal muscle it associates with theryanodine receptor RyR1 of thesarcoplasmic reticulum via a mechanical linkage. It senses thevoltage change caused by theend-plate potential from nervous stimulation and propagated by sodium channels asaction potentials to the T-tubules. It was previously thought that when the muscle depolarises, the calcium channel opens, allowing calcium in and activating RyR1, which mediates much greater calcium release from the sarcoplasmic reticulum. This is the first part of the process ofexcitation-contraction coupling, which ultimately causes the muscle to contract. Calcium entry through Cav1.1 is not required in skeletal muscle, as it is in cardiac muscle; Cav1.1 undergoes a conformational change which allosterically activates RyR1.[6]
Inhypokalemic periodic paralysis (HOKPP), the voltage sensors in domains 2 and 4 of Cav1.1 are mutated (loss-of-function), reducing the availability of the channel to sense depolarisation, and therefore it cannot activate the ryanodine receptor as efficiently. As a result, the muscle cannot contract very well and the patient is paralysed. The condition is hypokalemic because a low extracellular potassiumion concentration will cause the muscle to repolarise to theresting potential more quickly, so any calcium conductance that does occur cannot be sustained. It becomes more difficult to reach the threshold at which the muscle can contract, and even if this is reached then the muscle is more prone to relaxing. Because of this, the severity would be reduced if potassium ion concentrations are maintained. In contrast,hyperkalemic periodic paralysis refers to gain-of-function mutations in sodium channels that maintain muscle depolarisation and therefore are aggravated byhigh potassium ion concentrations.[7]
The EuropeanMalignant Hyperthermia Group accepts two mutations in CACNA1S as diagnostic for malignant hyperthermia.[8]
Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (2005). "International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels".Pharmacol. Rev.57 (4):411–25.doi:10.1124/pr.57.4.5.PMID16382099.S2CID10386627.
Tanabe T, Takeshima H, Mikami A, Flockerzi V, Takahashi H, Kangawa K, Kojima M, Matsuo H, Hirose T, Numa S (1987). "Primary structure of the receptor for calcium channel blockers from skeletal muscle".Nature.328 (6128):313–8.Bibcode:1987Natur.328..313T.doi:10.1038/328313a0.PMID3037387.S2CID4325355.
Hogan K, Powers PA, Gregg RG (1994). "Cloning of the human skeletal muscle alpha 1 subunit of the dihydropyridine-sensitive L-type calcium channel (CACNL1A3)".Genomics.24 (3):608–9.doi:10.1006/geno.1994.1677.PMID7713519.
Gregg RG, Couch F, Hogan K, Powers PA (1993). "Assignment of the human gene for the alpha 1 subunit of the skeletal muscle DHP-sensitive Ca2+ channel (CACNL1A3) to chromosome 1q31-q32".Genomics.15 (1):107–12.doi:10.1006/geno.1993.1017.PMID7916735.
Ptácek LJ, Tawil R, Griggs RC, Engel AG, Layzer RB, Kwieciński H, McManis PG, Santiago L, Moore M, Fouad G (1994). "Dihydropyridine receptor mutations cause hypokalemic periodic paralysis".Cell.77 (6):863–8.doi:10.1016/0092-8674(94)90135-X.PMID8004673.S2CID13538157.
Drouet B, Garcia L, Simon-Chazottes D, Mattei MG, Guénet JL, Schwartz A, Varadi G, Pinçon-Raymond M (1993). "The gene coding for the alpha 1 subunit of the skeletal dihydropyridine receptor (Cchl1a3 = mdg) maps to mouse chromosome 1 and human 1q32".Mamm. Genome.4 (9):499–503.doi:10.1007/BF00364784.PMID8118099.S2CID1386074.
Iles DE, Segers B, Olde Weghuis D, Suijkerbuijk R, Mikala G, Schwartz A, Wieringa B (1994). "Refined localization of the alpha 1-subunit of the skeletal muscle L-type voltage-dependent calcium channel (CACNL1A3) to human chromosome 1q32 by in situ hybridization".Genomics.19 (3):561–3.doi:10.1006/geno.1994.1106.PMID8188298.
Hogan K, Gregg RG, Powers PA (1996). "The structure of the gene encoding the human skeletal muscle alpha 1 subunit of the dihydropyridine-sensitive L-type calcium channel (CACNL1A3)".Genomics.31 (3):392–4.doi:10.1006/geno.1996.0066.PMID8838325.
Carsana A, Fortunato G, De Sarno C, Brancadoro V, Salvatore F (2003). "Identification of new polymorphisms in the CACNA1S gene".Clin. Chem. Lab. Med.41 (1):20–2.doi:10.1515/CCLM.2003.004.PMID12636044.S2CID20811090.
