UniProt functional annotation for Q13698



	UniProt functional annotation for Q13698

UniProt code: Q13698.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Pore-forming, alpha-1S subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents in skeletal muscle. Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle via their interaction with RYR1, which triggers Ca(2+) release from the sarcplasmic reticulum and ultimately results in muscle contraction. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. {ECO:0000250|UniProtKB:P07293}.

Activity regulation: Channel activity is blocked by dihydropyridines (DHP), phenylalkylamines, and by benzothiazepines. {ECO:0000250|UniProtKB:P07293}.

Subunit: Component of a calcium channel complex consisting of a pore- forming alpha subunit (CACNA1S) and the ancillary subunits CACNB1 or CACNB2, CACNG1 and CACNA2D1. The channel complex contains alpha, beta, gamma and delta subunits in a 1:1:1:1 ratio, i.e. it contains either CACNB1 or CACNB2 (By similarity). CACNA1S channel activity is modulated by the auxiliary subunits (CACNB1 or CACNB2, CACNG1 and CACNA2D1). Interacts with DYSF and JSRP1 (By similarity). Interacts with RYR1 (By similarity). Interacts with STAC, STAC2 and STAC3 (via their SH3 domains) (PubMed:29078335). Interacts with CALM (PubMed:19473981). {ECO:0000250|UniProtKB:P07293, ECO:0000250|UniProtKB:Q02789, ECO:0000269|PubMed:19473981, ECO:0000269|PubMed:29078335}.

Subcellular location: Cell membrane, sarcolemma, T-tubule {ECO:0000250|UniProtKB:P07293}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P07293}.

Tissue specificity: Skeletal muscle specific.

Domain: Each of the four internal repeats contains five hydrophobic transmembrane segments (S1, S2, S3, S5, S6) and one positively charged transmembrane segment (S4). S4 segments probably represent the voltage- sensor and are characterized by a series of positively charged amino acids at every third position. {ECO:0000250|UniProtKB:P07293}.

Domain: The loop between repeats II and III interacts with the ryanodine receptor, and is therefore important for calcium release from the endoplasmic reticulum necessary for muscle contraction. {ECO:0000250|UniProtKB:P07293}.

Ptm: The alpha-1S subunit is found in two isoforms in the skeletal muscle: a minor form of 212 kDa containing the complete amino acid sequence, and a major form of 190 kDa derived from the full-length form by post-translational proteolysis close to Phe-1690. {ECO:0000250|UniProtKB:P07293}.

Ptm: Phosphorylated. Phosphorylation by PKA activates the calcium channel. Both the minor and major forms are phosphorylated in vitro by PKA. Phosphorylation at Ser-1575 is involved in beta-adrenergic- mediated regulation of the channel. {ECO:0000250|UniProtKB:P07293}.

Disease: Periodic paralysis hypokalemic 1 (HOKPP1) [MIM:170400]: An autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels. {ECO:0000269|PubMed:17418573, ECO:0000269|PubMed:18162704, ECO:0000269|PubMed:19118277, ECO:0000269|PubMed:7987325, ECO:0000269|PubMed:8004673}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Malignant hyperthermia 5 (MHS5) [MIM:601887]: Autosomal dominant disorder that is potentially lethal in susceptible individuals on exposure to commonly used inhalational anesthetics and depolarizing muscle relaxants. {ECO:0000269|PubMed:9199552}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Disease: Thyrotoxic periodic paralysis 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. {ECO:0000269|PubMed:15001631}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity: Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1S subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Pore-forming, alpha-1S subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents in skeletal muscle. Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle via their interaction with RYR1, which triggers Ca(2+) release from the sarcplasmic reticulum and ultimately results in muscle contraction. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. {ECO:0000250\|UniProtKB:P07293}.


Activity regulation:		Channel activity is blocked by dihydropyridines (DHP), phenylalkylamines, and by benzothiazepines. {ECO:0000250\|UniProtKB:P07293}.
Subunit:		Component of a calcium channel complex consisting of a pore- forming alpha subunit (CACNA1S) and the ancillary subunits CACNB1 or CACNB2, CACNG1 and CACNA2D1. The channel complex contains alpha, beta, gamma and delta subunits in a 1:1:1:1 ratio, i.e. it contains either CACNB1 or CACNB2 (By similarity). CACNA1S channel activity is modulated by the auxiliary subunits (CACNB1 or CACNB2, CACNG1 and CACNA2D1). Interacts with DYSF and JSRP1 (By similarity). Interacts with RYR1 (By similarity). Interacts with STAC, STAC2 and STAC3 (via their SH3 domains) (PubMed:29078335). Interacts with CALM (PubMed:19473981). {ECO:0000250\|UniProtKB:P07293, ECO:0000250\|UniProtKB:Q02789, ECO:0000269\|PubMed:19473981, ECO:0000269\|PubMed:29078335}.
Subcellular location:		Cell membrane, sarcolemma, T-tubule {ECO:0000250\|UniProtKB:P07293}; Multi-pass membrane protein {ECO:0000250\|UniProtKB:P07293}.
Tissue specificity:		Skeletal muscle specific.
Domain:		Each of the four internal repeats contains five hydrophobic transmembrane segments (S1, S2, S3, S5, S6) and one positively charged transmembrane segment (S4). S4 segments probably represent the voltage- sensor and are characterized by a series of positively charged amino acids at every third position. {ECO:0000250\|UniProtKB:P07293}.
Domain:		The loop between repeats II and III interacts with the ryanodine receptor, and is therefore important for calcium release from the endoplasmic reticulum necessary for muscle contraction. {ECO:0000250\|UniProtKB:P07293}.
Ptm:		The alpha-1S subunit is found in two isoforms in the skeletal muscle: a minor form of 212 kDa containing the complete amino acid sequence, and a major form of 190 kDa derived from the full-length form by post-translational proteolysis close to Phe-1690. {ECO:0000250\|UniProtKB:P07293}.
Ptm:		Phosphorylated. Phosphorylation by PKA activates the calcium channel. Both the minor and major forms are phosphorylated in vitro by PKA. Phosphorylation at Ser-1575 is involved in beta-adrenergic- mediated regulation of the channel. {ECO:0000250\|UniProtKB:P07293}.
Disease:		Periodic paralysis hypokalemic 1 (HOKPP1) [MIM:170400]: An autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels. {ECO:0000269\|PubMed:17418573, ECO:0000269\|PubMed:18162704, ECO:0000269\|PubMed:19118277, ECO:0000269\|PubMed:7987325, ECO:0000269\|PubMed:8004673}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Malignant hyperthermia 5 (MHS5) [MIM:601887]: Autosomal dominant disorder that is potentially lethal in susceptible individuals on exposure to commonly used inhalational anesthetics and depolarizing muscle relaxants. {ECO:0000269\|PubMed:9199552}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Disease:		Thyrotoxic periodic paralysis 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. {ECO:0000269\|PubMed:15001631}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Similarity:		Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1S subfamily. {ECO:0000305}.