Channelpedia

Cav1.1

Description: calcium channel, voltage-dependent, L type, alpha 1S subunit
Gene: Cacna1s     Synonyms: cacna1s, cav1.1, ca1.1, MHS5, HOKPP, hypoPP, CCHL1A3, CACNL1A3

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Introduction

The voltage-gated Ca2+ channel CaV1.1 functions as a voltage sensor in skeletal muscle excitation-contraction (EC) coupling. (Tuluc [1227])

CACNA1 (also known as MHS5; HOKPP; TTPP1; Cav1.1; HOKPP1; hypoPP; CCHL1A3; CACNL1A3) encodes Cav1.1, 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.

http://www.ncbi.nlm.nih.gov/gene/779


Experimental data


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Gene

Only one CaV1.1 splice variant has so far been described in rabbit skeletal muscle (Perez-Reyes [1235]). Skipping of exon 29 shortens the extra-cellular loop connecting transmembrane domains IVS3 and IVS4. This loop is a conserved splicing site of CaV1 a1 subunits that has been shown to generate differentially distributed and functionally distinct channel variants. (Tuluc [1227]

RGD ID Chromosome Position Species
70983 - Rat
733918 1 137949478-138016399 Mouse
736857 1 201008640-201081694 Human

Cacna1s : calcium channel, voltage-dependent, L type, alpha 1S subunit


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Transcript

Acc No Sequence Length Source
NM_053873 n/A n/A NCBI
NM_001081023 n/A n/A NCBI
NM_014193 n/A n/A NCBI
NM_000069 n/A n/A NCBI

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Ontology


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Interaction

I-II loop of Ca(v)1.1 was identified as the domain interacting with caveolin-3, with an apparent affinity of 60nM. Couchoux et al [1228] showed a direct molecular interaction between caveolin-3 and the dihydropyridine receptor which is likely to underlie their functional link and whose loss might therefore be involved in pathophysiological mechanisms associated to muscle caveolinopathies.


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Protein


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Structure

See figure 1 in Striessnig et al [1230] for a detailed structure drawing of Cav1.1.


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Distribution

Cav1.1 in muscle cells is located in triad junctions in close apposition to the Ca2+ release channel (type 1 ryanodine receptor (RyR1)) in the sarcoplasmic reticulum (SR). (Tuluc [1227])


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Expression


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Functional

Cav1.1 and Cav1.2 subunits may substitute for Cav1.3 to maintain bone response to mechanical loading. (Zhao[1229])


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Kinetics

On depolarization of the surface membrane, CaV1.1 undergoes a conformational change that rapidly activates the Ca2+ release channel, presumably via protein-protein interactions. Ca2+ influx through the voltage-gated Ca2+ channel is not required for activation of skeletal muscle EC coupling. L-type Ca2+ currents through CaV1.1 activate very slowly and at more positive membrane potentials than EC coupling (for review, see Melzer et al. [1234]). Therefore, it is unlikely that during a short skeletal muscle action potential Ca2+ channels contribute significant amounts of Ca2+ to the transients that trigger contraction. (Tuluc [1227])

Cav1.1 channels (which also contain a γ-subunit) carry very slowly activating Ca2+ inward currents, too slow for providing Ca2+ to the contractile machinery in response to millisecond depolarizations eliciting muscle contraction. Although the fast conformational changes of their voltage-sensing domains induce pore opening very slowly, they are quickly transmitted to the sarcoplasmic reticulum (SR) ryanodine receptors (RyR1), thus serving as fast voltage sensors for SR Ca2+ release. This seems to be accomplished through a close physical association of Cav1.1 channels in the T- tubular membrane and RyR1 in the junctional SR of the skeletal muscle triads (Kugler [1236]).


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Model


References

Li J et al. Skeletal phenotype of mice with a null mutation in Cav 1.3 L-type calcium channel.
J Musculoskelet Neuronal Interact, 2010 Jun , 10 (180-7).

1233

Stroffekova K Ca2+/CaM-dependent inactivation of the skeletal muscle L-type Ca2+ channel (Cav1.1).
Pflugers Arch., 2008 Feb , 455 (873-84).

Melzer W et al. The role of Ca2+ ions in excitation-contraction coupling of skeletal muscle fibres.
Biochim. Biophys. Acta, 1995 May 8 , 1241 (59-116).


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Credits

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