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

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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

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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]

Species	NCBI gene ID	Chromosome	Position
Human	779	1	72914
Mouse	12292	1	67299
Rat	682930	13	70245

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Transcript

Species	NCBI accession	Length (nt)
Human	NM_000069.3	6028
Mouse	NM_014193.3	6278
Rat	NM_053873.1	6125

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Protein Isoforms

Species	Uniprot ID	Length (aa)
Human	Q13698	1873
Mouse	Q02789	1852
Rat	Q02485	1850

Isoforms

Transcript

Length (nt)

Protein

Length (aa)

Variant

Isoform

Known

NM_000069.3

6028

NP_000060.2

1873

Predicted

XM_005245478.4

5971

XP_005245535.1

1854

transcript variant X1

isoform X1

XM_054338645.1

5971

XP_054194620.1

1854

transcript variant X1

isoform X1

Known

NM_001081023.2

6341

NP_001074492.1

1852

transcript variant 2

isoform 2

NM_014193.3

6278

NP_055008.2

1831

transcript variant 1

isoform 1

NM_001402949.1

6043

NP_001389878.1

1850

isoform 3

Predicted

XM_006529106.4

6336

XP_006529169.1

1850

transcript variant X1

isoform X1

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Post-Translational Modifications

PTM

Position

Type

Modified residue

393

Phosphoserine

Modified residue

397

Phosphoserine

Modified residue

687

Phosphoserine; by PKA

Modified residue

1575

Phosphoserine; by PKA and CAMK2

Modified residue

1617

Phosphoserine; by PKA

Glycosylation

N-linked (GlcNAc...) asparagine

Glycosylation

257

N-linked (GlcNAc...) asparagine

Glycosylation

1141

N-linked (GlcNAc...) asparagine

Disulfide bond

Modified residue

393

Phosphoserine

Modified residue

397

Phosphoserine

Modified residue

687

Phosphoserine; by PKA

Modified residue

1575

Phosphoserine; by PKA and CAMK2

Modified residue

1579

Phosphothreonine

Modified residue

1617

Phosphoserine; by PKA

Glycosylation

N-linked (GlcNAc...) asparagine

Glycosylation

257

N-linked (GlcNAc...) asparagine

Glycosylation

1141

N-linked (GlcNAc...) asparagine

Disulfide bond

Modified residue

393

Phosphoserine

Modified residue

397

Phosphoserine

Modified residue

687

Phosphoserine; by PKA

Modified residue

1575

Phosphoserine; by PKA and CAMK2

Modified residue

1579

Phosphothreonine

Modified residue

1617

Phosphoserine; by PKA

Glycosylation

1141

N-linked (GlcNAc...) asparagine

Disulfide bond

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Structure

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

Cav1.1 predicted AlphaFold size

Species	Area (Å²)	Reference
Human	10735.86	source
Mouse	10741.46	source
Rat	11078.77	source

Methodology for AlphaFold size prediction and disclaimer are available here

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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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CNS Sub-cellular 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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Function

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

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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.

References

1227

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).

1228

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 , ().

1229

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).

1230

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 , ().

1231

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).

1232

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).

1233

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

1234

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).

1235

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).

1236

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).

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Credits

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/84/ , accessed on 2024 Apr 26

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