UniProt functional annotation for E9Q401



	UniProt functional annotation for E9Q401

UniProt code: E9Q401.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering cardiac muscle contraction. Aberrant channel activation can lead to cardiac arrhythmia. In cardiac myocytes, calcium release is triggered by increased Ca(2+) levels due to activation of the L-type calcium channel CACNA1C. The calcium channel activity is modulated by formation of heterotetramers with RYR3. Required for cellular calcium ion homeostasis. Required for embryonic heart development. {ECO:0000269|PubMed:10473538, ECO:0000269|PubMed:20431056, ECO:0000269|PubMed:21098440, ECO:0000269|PubMed:9628868}.

Activity regulation: Channel activity is modulated by the alkaloid ryanodine that binds to the open Ca-release channel with high affinity. At low concentrations, ryanodine maintains the channel in an open conformation. High ryanodine concentrations inhibit channel activity. Channel activity is regulated by calmodulin (CALM). The calcium release is activated by increased cytoplasmic calcium levels, by nitric oxyde (NO), caffeine and ATP. Channel activity is inhibited by magnesium ions, possibly by competition for calcium binding sites (By similarity). {ECO:0000250|UniProtKB:P11716}.

Subunit: Homotetramer. Can also form heterotetramers with RYR1 and RYR3. Interacts with CALM and S100A1; these interactions regulate channel activity. Identified in a complex composed of RYR2, FKBP1B, PKA catalytic subunit, PRKAR2A, AKAP6, and the protein phosphatases PP2A and PP1. Interacts directly with FKBP1B, PKA, PP1 and PP2A (By similarity). Interacts with FKBP1A and FKBP1B; these interactions may stabilize the channel in its closed state and prevent Ca(2+) leaks. Interacts with SELENON (By similarity). Identified in a complex, composed of FSD2, CMYA5 and RYR2 (PubMed:28740084). {ECO:0000250|UniProtKB:P30957, ECO:0000250|UniProtKB:Q92736, ECO:0000269|PubMed:10473538, ECO:0000269|PubMed:20431056, ECO:0000269|PubMed:21098440, ECO:0000269|PubMed:28740084}.

Subcellular location: Sarcoplasmic reticulum membrane {ECO:0000305|PubMed:10473538}; Multi-pass membrane protein {ECO:0000305|PubMed:10473538}. Membrane {ECO:0000305|PubMed:10473538}; Multi-pass membrane protein {ECO:0000305|PubMed:10473538}. Sarcoplasmic reticulum {ECO:0000250|UniProtKB:P30957}. Note=The number of predicted transmembrane domains varies between orthologs, but both N-terminus and C-terminus seem to be cytoplasmic. {ECO:0000250}.

Tissue specificity: Highly expressed in heart, lung, cerebellum and brain. Detected at lower levels in adrenal gland, stomach, thymus, esophagus and ovary. {ECO:0000269|PubMed:7621815, ECO:0000269|PubMed:7876312}.

Domain: The calcium release channel activity resides in the C-terminal region while the remaining part of the protein resides in the cytoplasm. {ECO:0000305}.

Ptm: Channel activity is modulated by phosphorylation. Phosphorylation at Ser-2807 and Ser-2813 increases the open probability of the calcium channel. Phosphorylation is increased in failing heart, leading to calcium leaks and increased cytoplasmic Ca(2+) levels. {ECO:0000269|PubMed:17693412, ECO:0000269|PubMed:20431056, ECO:0000269|PubMed:21098440}.

Ptm: Phosphorylation at Ser-2030 by PKA enhances the response to lumenal calcium. {ECO:0000269|PubMed:17693412}.

Disruption phenotype: Embryonically lethal. Embryos die at about 10 dpc, due to defects in heart tube development. Cardiac myotubes display enlarged rough endoplasmic reticulum and cytoplasmic vesicles that contain high levels of Ca(2+). {ECO:0000269|PubMed:9628868}.

Similarity: Belongs to the ryanodine receptor (TC 1.A.3.1) family. RYR2 subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering cardiac muscle contraction. Aberrant channel activation can lead to cardiac arrhythmia. In cardiac myocytes, calcium release is triggered by increased Ca(2+) levels due to activation of the L-type calcium channel CACNA1C. The calcium channel activity is modulated by formation of heterotetramers with RYR3. Required for cellular calcium ion homeostasis. Required for embryonic heart development. {ECO:0000269\|PubMed:10473538, ECO:0000269\|PubMed:20431056, ECO:0000269\|PubMed:21098440, ECO:0000269\|PubMed:9628868}.


Activity regulation:		Channel activity is modulated by the alkaloid ryanodine that binds to the open Ca-release channel with high affinity. At low concentrations, ryanodine maintains the channel in an open conformation. High ryanodine concentrations inhibit channel activity. Channel activity is regulated by calmodulin (CALM). The calcium release is activated by increased cytoplasmic calcium levels, by nitric oxyde (NO), caffeine and ATP. Channel activity is inhibited by magnesium ions, possibly by competition for calcium binding sites (By similarity). {ECO:0000250\|UniProtKB:P11716}.
Subunit:		Homotetramer. Can also form heterotetramers with RYR1 and RYR3. Interacts with CALM and S100A1; these interactions regulate channel activity. Identified in a complex composed of RYR2, FKBP1B, PKA catalytic subunit, PRKAR2A, AKAP6, and the protein phosphatases PP2A and PP1. Interacts directly with FKBP1B, PKA, PP1 and PP2A (By similarity). Interacts with FKBP1A and FKBP1B; these interactions may stabilize the channel in its closed state and prevent Ca(2+) leaks. Interacts with SELENON (By similarity). Identified in a complex, composed of FSD2, CMYA5 and RYR2 (PubMed:28740084). {ECO:0000250\|UniProtKB:P30957, ECO:0000250\|UniProtKB:Q92736, ECO:0000269\|PubMed:10473538, ECO:0000269\|PubMed:20431056, ECO:0000269\|PubMed:21098440, ECO:0000269\|PubMed:28740084}.
Subcellular location:		Sarcoplasmic reticulum membrane {ECO:0000305\|PubMed:10473538}; Multi-pass membrane protein {ECO:0000305\|PubMed:10473538}. Membrane {ECO:0000305\|PubMed:10473538}; Multi-pass membrane protein {ECO:0000305\|PubMed:10473538}. Sarcoplasmic reticulum {ECO:0000250\|UniProtKB:P30957}. Note=The number of predicted transmembrane domains varies between orthologs, but both N-terminus and C-terminus seem to be cytoplasmic. {ECO:0000250}.
Tissue specificity:		Highly expressed in heart, lung, cerebellum and brain. Detected at lower levels in adrenal gland, stomach, thymus, esophagus and ovary. {ECO:0000269\|PubMed:7621815, ECO:0000269\|PubMed:7876312}.
Domain:		The calcium release channel activity resides in the C-terminal region while the remaining part of the protein resides in the cytoplasm. {ECO:0000305}.
Ptm:		Channel activity is modulated by phosphorylation. Phosphorylation at Ser-2807 and Ser-2813 increases the open probability of the calcium channel. Phosphorylation is increased in failing heart, leading to calcium leaks and increased cytoplasmic Ca(2+) levels. {ECO:0000269\|PubMed:17693412, ECO:0000269\|PubMed:20431056, ECO:0000269\|PubMed:21098440}.
Ptm:		Phosphorylation at Ser-2030 by PKA enhances the response to lumenal calcium. {ECO:0000269\|PubMed:17693412}.
Disruption phenotype:		Embryonically lethal. Embryos die at about 10 dpc, due to defects in heart tube development. Cardiac myotubes display enlarged rough endoplasmic reticulum and cytoplasmic vesicles that contain high levels of Ca(2+). {ECO:0000269\|PubMed:9628868}.
Similarity:		Belongs to the ryanodine receptor (TC 1.A.3.1) family. RYR2 subfamily. {ECO:0000305}.