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Cav1.1

CACNA1S
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCACNA1S, CACNL1A3, CCHL1A3, Cav1.1, HOKPP, HOKPP1, MHS5, TTPP1, hypoPP, calcium voltage-gated channel subunit alpha1 S, DHPR
External IDsOMIM: 114208 MGI: 88294 HomoloGene: 37257 GeneCards: CACNA1S
Gene location (Human)
Chromosome 1 (human)
Chr.Chromosome 1 (human)[1]
Chromosome 1 (human)
Genomic location for CACNA1S
Genomic location for CACNA1S
Band1q32.1Start201,039,512 bp[1]
End201,112,451 bp[1]
RNA expression pattern
PBB GE CACNA1S 217515 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000069

NM_001081023
NM_014193

RefSeq (protein)

NP_000060

n/a

Location (UCSC)Chr 1: 201.04 – 201.11 MbChr 1: 136.05 – 136.12 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cav1.1 also known as the calcium channel, voltage-dependent, L type, alpha 1S subunit, (CACNA1S), is a protein which in humans is encoded by the CACNA1S gene.[5] It is also known as CACNL1A3 and the dihydropyridine receptor (DHPR, so named due to the blocking action DHP has on it).

Function

This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility.[5]

Cav1.1 is a voltage-dependent calcium channel found in the transverse tubule of muscles. In skeletal muscle it associates with the ryanodine receptor RyR1 of the sarcoplasmic reticulum via a mechanical linkage. It senses the voltage change caused by the end-plate potential from nervous stimulation and propagated by sodium channels as action 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 of excitation-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]

Clinical significance

In hypokalemic 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 potassium ion concentration will cause the muscle to repolarise to the resting 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 by high potassium ion concentrations.[7]

The European Malignant Hyperthermia Group accepts two mutations in CACNA1S as diagnostic for malignant hyperthermia.[8]

Blockers

Cav1.1 is blocked by dihydropyridine.

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000081248 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026407 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: CACNA1S calcium channel, voltage-dependent, L type, alpha 1S subunit".
  6. ^ Proenza C, O'Brien J, Nakai J, Mukherjee S, Allen PD, Beam KG (February 2002). "Identification of a region of RyR1 that participates in allosteric coupling with the alpha(1S) (Ca(V)1.1) II-III loop". J. Biol. Chem. 277 (8): 6530–5. doi:10.1074/jbc.M106471200. PMID 11726651.
  7. ^ Jurkat-Rott K, Lehmann-Horn F (August 2005). "Muscle channelopathies and critical points in functional and genetic studies". J. Clin. Invest. 115 (8): 2000–9. doi:10.1172/JCI25525. PMC 1180551. PMID 16075040.
  8. ^ "Archived copy". Archived from the original on 2016-03-21. Retrieved 2015-05-14.CS1 maint: archived copy as title (link)

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.