6b27

Structural highlights

Disease

[CAC1S_HUMAN] Defects in CACNA1S are the cause of periodic paralysis hypokalemic type 1 (HOKPP1) [MIM:170400]; also designated HYPOPP. HOKPP1 is an autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels.^{[1] [2] [3] [4] [5]} Genetic variations in CACNA1S are the cause of susceptibility to malignant hyperthermia 5 (MHS5) [MIM:601887]; an autosomal dominant disorder that is potentially lethal in susceptible individuals on exposure to commonly used inhalational anesthetics and depolarizing muscle relaxants.^[6] Defects in CACNA1S are the cause of susceptibility to thyrotoxic periodic paralysis type 1 (TTPP1) [MIM:188580]. A sporadic muscular disorder characterized by episodic weakness and hypokalemia during a thyrotoxic state. It is clinically similar to hereditary hypokalemic periodic paralysis, except for the fact that hyperthyroidism is an absolute requirement for disease manifestation. The disease presents with recurrent episodes of acute muscular weakness of the four extremities that vary in severity from paresis to complete paralysis. Attacks are triggered by ingestion of a high carbohydrate load or strenuous physical activity followed by a period of rest. Thyrotoxic periodic paralysis can occur in association with any cause of hyperthyroidism, but is most commonly associated with Graves disease.^[7]

Function

[CAC1S_HUMAN] Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1S gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin-GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle.

References

1. ↑ Ptacek LJ, Tawil R, Griggs RC, Engel AG, Layzer RB, Kwiecinski H, McManis PG, Santiago L, Moore M, Fouad G, et al.. Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell. 1994 Jun 17;77(6):863-8. PMID:8004673
2. ↑ Jurkat-Rott K, Lehmann-Horn F, Elbaz A, Heine R, Gregg RG, Hogan K, Powers PA, Lapie P, Vale-Santos JE, Weissenbach J, et al.. A calcium channel mutation causing hypokalemic periodic paralysis. Hum Mol Genet. 1994 Aug;3(8):1415-9. PMID:7987325
3. ↑ Kim JB, Kim MH, Lee SJ, Kim DJ, Lee BC. The genotype and clinical phenotype of Korean patients with familial hypokalemic periodic paralysis. J Korean Med Sci. 2007 Dec;22(6):946-51. PMID:18162704
4. ↑ Houinato D, Laleye A, Adjien C, Adjagba M, Sternberg D, Hilbert P, Vallat JM, Darboux RB, Funalot B, Avode DG. Hypokalaemic periodic paralysis due to the CACNA1S R1239H mutation in a large African family. Neuromuscul Disord. 2007 May;17(5):419-22. Epub 2007 Apr 5. PMID:17418573 doi:10.1016/j.nmd.2007.01.020
5. ↑ Matthews E, Labrum R, Sweeney MG, Sud R, Haworth A, Chinnery PF, Meola G, Schorge S, Kullmann DM, Davis MB, Hanna MG. Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology. 2009 May 5;72(18):1544-7. Epub 2008 Dec 31. PMID:19118277 doi:01.wnl.0000342387.65477.46
6. ↑ Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet. 1997 Jun;60(6):1316-25. PMID:9199552
7. ↑ Kung AW, Lau KS, Fong GC, Chan V. Association of novel single nucleotide polymorphisms in the calcium channel alpha 1 subunit gene (Ca(v)1.1) and thyrotoxic periodic paralysis. J Clin Endocrinol Metab. 2004 Mar;89(3):1340-5. PMID:15001631