Cav1.1
Description: calcium channel, voltage-dependent, L type, alpha 1S subunit Gene: Cacna1s Alias: cacna1s, cav1.1, ca1.1, MHS5, HOKPP, hypoPP, CCHL1A3, CACNL1A3
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
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]
Transcript
Species | NCBI accession | Length (nt) | |
---|---|---|---|
Human | NM_000069.3 | 6028 | |
Mouse | NM_014193.3 | 6278 | |
Rat | NM_053873.1 | 6125 |
Protein Isoforms
Isoforms
Post-Translational Modifications
See figure 1 in Striessnig et al [1230] for a detailed structure drawing of Cav1.1.
Cav1.1 predicted AlphaFold size
Methodology for AlphaFold size prediction and disclaimer are available here
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]).
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])
Cav1.1 and Cav1.2 subunits may substitute for Cav1.3 to maintain bone response to mechanical loading. (Zhao[1229])
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.
References
Tuluc P
et al.
A CaV1.1 Ca2+ channel splice variant with high conductance and voltage-sensitivity alters EC coupling in developing skeletal muscle.
Biophys. J.,
2009
Jan
, 96 (35-44).
Couchoux H
et al.
Caveolin-3 is a direct molecular partner of the Ca(v)1.1 subunit of the skeletal muscle L-type calcium channel.
,
2011
Jan
22
, ().
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).
Striessnig J
et al.
Channelopathies in Ca(v)1.1, Ca (v)1.3, and Ca (v)1.4 voltage-gated L-type Ca (2+) channels.
,
2010
Mar
7
, ().
Ohrtman J
et al.
Sequence differences in the IQ motifs of CaV1.1 and CaV1.2 strongly impact calmodulin binding and calcium-dependent inactivation.
J. Biol. Chem.,
2008
Oct
24
, 283 (29301-11).
Strube C
Absence of regulation of the T-type calcium current by Cav1.1, beta1a and gamma1 dihydropyridine receptor subunits in skeletal muscle cells.
Pflugers Arch.,
2008
Feb
, 455 (921-7).
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).
Perez-Reyes E
et al.
Molecular diversity of L-type calcium channels. Evidence for alternative splicing of the transcripts of three non-allelic genes.
J. Biol. Chem.,
1990
Nov
25
, 265 (20430-6).
Kugler G
et al.
Structural requirements of the dihydropyridine receptor alpha1S II-III loop for skeletal-type excitation-contraction coupling.
J. Biol. Chem.,
2004
Feb
6
, 279 (4721-8).
Credits
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