UniProt functional annotation for P11716



	UniProt functional annotation for P11716

UniProt code: P11716.

Organism: Oryctolagus cuniculus (Rabbit).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.

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 muscle contraction following depolarization of T-tubules (PubMed:3722165, PubMed:10388749, PubMed:10097181, PubMed:12732639, PubMed:22036948, PubMed:26245150, PubMed:27662087). Repeated very high- level exercise increases the open probability of the channel and leads to Ca(2+) leaking into the cytoplasm (By similarity). Can also mediate the release of Ca(2+) from intracellular stores in neurons, and may thereby promote prolonged Ca(2+) signaling in the brain. Required for normal embryonic development of muscle fibers and skeletal muscle. Required for normal heart morphogenesis, skin development and ossification during embryogenesis (By similarity). {ECO:0000250|UniProtKB:E9PZQ0, ECO:0000269|PubMed:10388749, ECO:0000269|PubMed:12732639, ECO:0000269|PubMed:22036948, ECO:0000269|PubMed:27662087, ECO:0000305|PubMed:10097181, ECO:0000305|PubMed:26245150, ECO:0000305|PubMed:3722165}.

Activity regulation: Channel activity is modulated by the alkaloid ryanodine that binds to the open Ca-release channel with high affinity (PubMed:27662087). At low concentrations, ryanodine maintains the channel in an open conformation (PubMed:27662087). High ryanodine concentrations inhibit channel activity (PubMed:27662087). Channel activity is regulated by calmodulin (CALM). The calcium release is activated by increased cytoplasmic calcium levels, by nitric oxyde (NO), caffeine and ATP (PubMed:12732639, PubMed:22036948, PubMed:26245150, PubMed:27662087). Channel activity is inhibited by magnesium ions, possibly by competition for calcium binding sites (PubMed:12732639). {ECO:0000269|PubMed:12732639, ECO:0000269|PubMed:22036948, ECO:0000269|PubMed:26245150, ECO:0000269|PubMed:27662087}.

Subunit: Homotetramer (PubMed:10097181, PubMed:15908964, PubMed:17027503, PubMed:18621707, PubMed:25470059, PubMed:25517095, PubMed:27662087, PubMed:27573175, PubMed:27468892). Can also form heterotetramers with RYR2 (PubMed:12213830). Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1). Repeated very high-level exercise decreases interaction with PDE4D and protein phosphatase 1 (PP1) (By similarity). Interacts with CALM; CALM with bound calcium inhibits the RYR1 channel activity (PubMed:10601232, PubMed:11562475, PubMed:17027503). Interacts with S100A1 (By similarity). Interacts with FKBP1A; this stabilizes the closed conformation of the channel (PubMed:7669046, PubMed:10603943, PubMed:26245150, PubMed:25517095, PubMed:27468892). Interacts with CACNA1S; interaction with CACNA1S is important for activation of the RYR1 channel (PubMed:10388749). Interacts with CACNB1 (PubMed:21320436). Interacts with TRDN and ASPH; these interactions stimulate RYR1 channel activity (PubMed:9737879, PubMed:19398037). Interacts with SELENON (PubMed:18713863). Interacts with scorpion calcins (AC P0DPT1; AC P0DM30; AC A0A1L4BJ42; AC P59868; AC P60254; AC B8QG00; AC L0GBR1; AC P60252; AC P60253) (PubMed:27114612). {ECO:0000250|UniProtKB:E9PZQ0, ECO:0000250|UniProtKB:P21817, ECO:0000269|PubMed:10097181, ECO:0000269|PubMed:10388749, ECO:0000269|PubMed:10601232, ECO:0000269|PubMed:10603943, ECO:0000269|PubMed:11562475, ECO:0000269|PubMed:12213830, ECO:0000269|PubMed:15908964, ECO:0000269|PubMed:17027503, ECO:0000269|PubMed:18621707, ECO:0000269|PubMed:18713863, ECO:0000269|PubMed:19398037, ECO:0000269|PubMed:21320436, ECO:0000269|PubMed:25470059, ECO:0000269|PubMed:25517095, ECO:0000269|PubMed:26245150, ECO:0000269|PubMed:27468892, ECO:0000269|PubMed:27573175, ECO:0000269|PubMed:27662087, ECO:0000269|PubMed:7669046, ECO:0000269|PubMed:9737879}.

Subcellular location: Sarcoplasmic reticulum membrane {ECO:0000269|PubMed:12486242, ECO:0000269|PubMed:25517095, ECO:0000269|PubMed:2725677, ECO:0000269|PubMed:27468892, ECO:0000269|PubMed:27573175, ECO:0000269|PubMed:27662087, ECO:0000269|PubMed:3722165}; Multi-pass membrane protein {ECO:0000269|PubMed:25470059, ECO:0000269|PubMed:25517095, ECO:0000269|PubMed:27468892, ECO:0000269|PubMed:27573175, ECO:0000269|PubMed:27662087}. Sarcoplasmic reticulum {ECO:0000269|PubMed:18713863}. Membrane {ECO:0000269|PubMed:12732639}; Multi-pass membrane protein {ECO:0000269|PubMed:25470059, ECO:0000269|PubMed:25517095, ECO:0000269|PubMed:27468892, ECO:0000269|PubMed:27573175, ECO:0000269|PubMed:27662087}. Note=The number of predicted transmembrane domains varies between orthologs, but the 3D-structures show the presence of six transmembrane regions. Both N-terminus and C-terminus are cytoplasmic. {ECO:0000269|PubMed:12486242, ECO:0000269|PubMed:25470059, ECO:0000269|PubMed:27468892, ECO:0000269|PubMed:27573175, ECO:0000269|PubMed:27662087}.

Tissue specificity: Detected in skeletal muscle (at protein level) (PubMed:2725677, PubMed:3722165, PubMed:25470059, PubMed:25517095, PubMed:27573175, PubMed:27468892). Fast- or slow-twitch skeletal muscle. {ECO:0000269|PubMed:15908964, ECO:0000269|PubMed:25470059, ECO:0000269|PubMed:25517095, ECO:0000269|PubMed:2725677, ECO:0000269|PubMed:27468892, ECO:0000269|PubMed:27573175, ECO:0000269|PubMed:3722165, ECO:0000269|PubMed:7669046}.

Domain: The calcium release channel activity resides in the C-terminal region while the remaining part of the protein constitutes the 'foot' structure spanning the junctional gap between the sarcoplasmic reticulum (SR) and the T-tubule (PubMed:2725677, PubMed:25517095, PubMed:27662087, PubMed:27573175, PubMed:27468892). Pore opening is mediated via the cytoplasmic calcium-binding domains that mediate a small rotation of the channel-forming transmembrane regions that then leads to channel opening (PubMed:27468892). {ECO:0000269|PubMed:25517095, ECO:0000269|PubMed:2725677, ECO:0000269|PubMed:27468892, ECO:0000269|PubMed:27573175, ECO:0000269|PubMed:27662087}.

Ptm: The N-terminus is blocked.

Ptm: Channel activity is modulated by phosphorylation. Phosphorylation at Ser-2843 may increase channel activity. Repeated very high-level exercise increases phosphorylation at Ser-2843. {ECO:0000250|UniProtKB:P21817}.

Ptm: Activated by reversible S-nitrosylation (PubMed:22036948). Repeated very high-level exercise increases S-nitrosylation (By similarity). {ECO:0000250|UniProtKB:P21817, ECO:0000269|PubMed:22036948}.

Miscellaneous: Coexpression of normal and mutant Thr-4897 RYR1 in a 1:1 ratio produces RYR1 channels with normal halothane and caffeine sensitivities, but maximal levels of Ca(2+) release are reduced by 67%. Binding of [3H]ryanodine indicates that the heterozygous channel is activated by Ca(2+) concentrations 4-fold lower than normal. Single- cell analysis of cotransfected cells shows a significantly increased resting cytoplasmic Ca(2+) level and a significantly reduced luminal Ca(2+) level. These data indicated a leaky channel, possibly caused by a reduction in the Ca(2+) concentration required for channel activation. {ECO:0000269|PubMed:10097181}.

Similarity: Belongs to the ryanodine receptor (TC 1.A.3.1) family. RYR1 subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Oryctolagus cuniculus (Rabbit).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.



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 muscle contraction following depolarization of T-tubules (PubMed:3722165, PubMed:10388749, PubMed:10097181, PubMed:12732639, PubMed:22036948, PubMed:26245150, PubMed:27662087). Repeated very high- level exercise increases the open probability of the channel and leads to Ca(2+) leaking into the cytoplasm (By similarity). Can also mediate the release of Ca(2+) from intracellular stores in neurons, and may thereby promote prolonged Ca(2+) signaling in the brain. Required for normal embryonic development of muscle fibers and skeletal muscle. Required for normal heart morphogenesis, skin development and ossification during embryogenesis (By similarity). {ECO:0000250\|UniProtKB:E9PZQ0, ECO:0000269\|PubMed:10388749, ECO:0000269\|PubMed:12732639, ECO:0000269\|PubMed:22036948, ECO:0000269\|PubMed:27662087, ECO:0000305\|PubMed:10097181, ECO:0000305\|PubMed:26245150, ECO:0000305\|PubMed:3722165}.


Activity regulation:		Channel activity is modulated by the alkaloid ryanodine that binds to the open Ca-release channel with high affinity (PubMed:27662087). At low concentrations, ryanodine maintains the channel in an open conformation (PubMed:27662087). High ryanodine concentrations inhibit channel activity (PubMed:27662087). Channel activity is regulated by calmodulin (CALM). The calcium release is activated by increased cytoplasmic calcium levels, by nitric oxyde (NO), caffeine and ATP (PubMed:12732639, PubMed:22036948, PubMed:26245150, PubMed:27662087). Channel activity is inhibited by magnesium ions, possibly by competition for calcium binding sites (PubMed:12732639). {ECO:0000269\|PubMed:12732639, ECO:0000269\|PubMed:22036948, ECO:0000269\|PubMed:26245150, ECO:0000269\|PubMed:27662087}.
Subunit:		Homotetramer (PubMed:10097181, PubMed:15908964, PubMed:17027503, PubMed:18621707, PubMed:25470059, PubMed:25517095, PubMed:27662087, PubMed:27573175, PubMed:27468892). Can also form heterotetramers with RYR2 (PubMed:12213830). Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1). Repeated very high-level exercise decreases interaction with PDE4D and protein phosphatase 1 (PP1) (By similarity). Interacts with CALM; CALM with bound calcium inhibits the RYR1 channel activity (PubMed:10601232, PubMed:11562475, PubMed:17027503). Interacts with S100A1 (By similarity). Interacts with FKBP1A; this stabilizes the closed conformation of the channel (PubMed:7669046, PubMed:10603943, PubMed:26245150, PubMed:25517095, PubMed:27468892). Interacts with CACNA1S; interaction with CACNA1S is important for activation of the RYR1 channel (PubMed:10388749). Interacts with CACNB1 (PubMed:21320436). Interacts with TRDN and ASPH; these interactions stimulate RYR1 channel activity (PubMed:9737879, PubMed:19398037). Interacts with SELENON (PubMed:18713863). Interacts with scorpion calcins (AC P0DPT1; AC P0DM30; AC A0A1L4BJ42; AC P59868; AC P60254; AC B8QG00; AC L0GBR1; AC P60252; AC P60253) (PubMed:27114612). {ECO:0000250\|UniProtKB:E9PZQ0, ECO:0000250\|UniProtKB:P21817, ECO:0000269\|PubMed:10097181, ECO:0000269\|PubMed:10388749, ECO:0000269\|PubMed:10601232, ECO:0000269\|PubMed:10603943, ECO:0000269\|PubMed:11562475, ECO:0000269\|PubMed:12213830, ECO:0000269\|PubMed:15908964, ECO:0000269\|PubMed:17027503, ECO:0000269\|PubMed:18621707, ECO:0000269\|PubMed:18713863, ECO:0000269\|PubMed:19398037, ECO:0000269\|PubMed:21320436, ECO:0000269\|PubMed:25470059, ECO:0000269\|PubMed:25517095, ECO:0000269\|PubMed:26245150, ECO:0000269\|PubMed:27468892, ECO:0000269\|PubMed:27573175, ECO:0000269\|PubMed:27662087, ECO:0000269\|PubMed:7669046, ECO:0000269\|PubMed:9737879}.
Subcellular location:		Sarcoplasmic reticulum membrane {ECO:0000269\|PubMed:12486242, ECO:0000269\|PubMed:25517095, ECO:0000269\|PubMed:2725677, ECO:0000269\|PubMed:27468892, ECO:0000269\|PubMed:27573175, ECO:0000269\|PubMed:27662087, ECO:0000269\|PubMed:3722165}; Multi-pass membrane protein {ECO:0000269\|PubMed:25470059, ECO:0000269\|PubMed:25517095, ECO:0000269\|PubMed:27468892, ECO:0000269\|PubMed:27573175, ECO:0000269\|PubMed:27662087}. Sarcoplasmic reticulum {ECO:0000269\|PubMed:18713863}. Membrane {ECO:0000269\|PubMed:12732639}; Multi-pass membrane protein {ECO:0000269\|PubMed:25470059, ECO:0000269\|PubMed:25517095, ECO:0000269\|PubMed:27468892, ECO:0000269\|PubMed:27573175, ECO:0000269\|PubMed:27662087}. Note=The number of predicted transmembrane domains varies between orthologs, but the 3D-structures show the presence of six transmembrane regions. Both N-terminus and C-terminus are cytoplasmic. {ECO:0000269\|PubMed:12486242, ECO:0000269\|PubMed:25470059, ECO:0000269\|PubMed:27468892, ECO:0000269\|PubMed:27573175, ECO:0000269\|PubMed:27662087}.
Tissue specificity:		Detected in skeletal muscle (at protein level) (PubMed:2725677, PubMed:3722165, PubMed:25470059, PubMed:25517095, PubMed:27573175, PubMed:27468892). Fast- or slow-twitch skeletal muscle. {ECO:0000269\|PubMed:15908964, ECO:0000269\|PubMed:25470059, ECO:0000269\|PubMed:25517095, ECO:0000269\|PubMed:2725677, ECO:0000269\|PubMed:27468892, ECO:0000269\|PubMed:27573175, ECO:0000269\|PubMed:3722165, ECO:0000269\|PubMed:7669046}.
Domain:		The calcium release channel activity resides in the C-terminal region while the remaining part of the protein constitutes the 'foot' structure spanning the junctional gap between the sarcoplasmic reticulum (SR) and the T-tubule (PubMed:2725677, PubMed:25517095, PubMed:27662087, PubMed:27573175, PubMed:27468892). Pore opening is mediated via the cytoplasmic calcium-binding domains that mediate a small rotation of the channel-forming transmembrane regions that then leads to channel opening (PubMed:27468892). {ECO:0000269\|PubMed:25517095, ECO:0000269\|PubMed:2725677, ECO:0000269\|PubMed:27468892, ECO:0000269\|PubMed:27573175, ECO:0000269\|PubMed:27662087}.
Ptm:		The N-terminus is blocked.
Ptm:		Channel activity is modulated by phosphorylation. Phosphorylation at Ser-2843 may increase channel activity. Repeated very high-level exercise increases phosphorylation at Ser-2843. {ECO:0000250\|UniProtKB:P21817}.
Ptm:		Activated by reversible S-nitrosylation (PubMed:22036948). Repeated very high-level exercise increases S-nitrosylation (By similarity). {ECO:0000250\|UniProtKB:P21817, ECO:0000269\|PubMed:22036948}.
Miscellaneous:		Coexpression of normal and mutant Thr-4897 RYR1 in a 1:1 ratio produces RYR1 channels with normal halothane and caffeine sensitivities, but maximal levels of Ca(2+) release are reduced by 67%. Binding of [3H]ryanodine indicates that the heterozygous channel is activated by Ca(2+) concentrations 4-fold lower than normal. Single- cell analysis of cotransfected cells shows a significantly increased resting cytoplasmic Ca(2+) level and a significantly reduced luminal Ca(2+) level. These data indicated a leaky channel, possibly caused by a reduction in the Ca(2+) concentration required for channel activation. {ECO:0000269\|PubMed:10097181}.
Similarity:		Belongs to the ryanodine receptor (TC 1.A.3.1) family. RYR1 subfamily. {ECO:0000305}.