UniProt functional annotation for O35433



	UniProt functional annotation for O35433

UniProt code: O35433.

Organism: Rattus norvegicus (Rat).

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

Function: Ligand-activated non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli. Seems to mediate proton influx and may be involved in intracellular acidosis in nociceptive neurons. Involved in mediation of inflammatory pain and hyperalgesia. Sensitized by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases, which involves PKC isozymes and PCL. Activation by vanilloids, like capsaicin, and temperatures higher than 42 degrees Celsius, exhibits a time- and Ca(2+)-dependent outward rectification, followed by a long-lasting refractory state. Mild extracellular acidic pH (6.5) potentiates channel activation by noxious heat and vanilloids, whereas acidic conditions (pH <6) directly activate the channel. Can be activated by endogenous compounds, including 12-hydroperoxytetraenoic acid and bradykinin. Acts as ionotropic endocannabinoid receptor with central neuromodulatory effects. Triggers a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamine in the hippocampus and nucleus accumbens by affecting AMPA receptors endocytosis. {ECO:0000269|PubMed:11140687, ECO:0000269|PubMed:11418861, ECO:0000269|PubMed:11578842, ECO:0000269|PubMed:12095983, ECO:0000269|PubMed:12194871, ECO:0000269|PubMed:12764195, ECO:0000269|PubMed:12808128, ECO:0000269|PubMed:14523239, ECO:0000269|PubMed:14630912, ECO:0000269|PubMed:15173182, ECO:0000269|PubMed:17582331, ECO:0000269|PubMed:20510930, ECO:0000269|PubMed:21076423, ECO:0000269|PubMed:23109716, ECO:0000269|PubMed:24305160, ECO:0000269|PubMed:9349813}.

Function: [Isoform 3]: Does not display channel activity in response to noxious chemical compounds, such as capsaicin and the vanilloid resiniferatoxin. Channel activity is not elicited by mildly acidic extracellular pH, and only slight channel activity is observed in response to noxiuos heat stimuli. {ECO:0000269|PubMed:10644739}.

Activity regulation: Channel activity is activated via the interaction with PIRT and phosphatidylinositol 4,5-bisphosphate (PIP2). Both PIRT and PIP2 are required to activate channel activity (By similarity). The channel is sensitized by ATP binding. Repeated stimulation with capsaicin gives rise to progressively smaller responses, due to desensitization. This desensitization is triggered by the influx of calcium ions and is inhibited by elevated ATP levels. Ca(2+) and CALM displace ATP from its binding site and trigger a conformation change that leads to a closed, desensitized channel. Intracellular PIP2 inhibits desensitization. The double-knot toxin (DkTx) from the Chinese earth tiger tarantula activates the channel and traps it in an open conformation. The Scolopendra mutilans RhTx toxin potentiates the heat activation pathway mediated by this channel by binding to the charge- rich outer pore region (in an activated state) (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:Q704Y3, ECO:0000269|PubMed:17582331, ECO:0000269|PubMed:20510930, ECO:0000269|PubMed:23109716}.

Subunit: Interacts with PIRT (By similarity). Homotetramer (PubMed:15190102, PubMed:24305160, PubMed:24305161, PubMed:27281200). May also form a heteromeric channel with TRPV3 (By similarity). Interacts with CALM, PRKCM and CSK (PubMed:12808128, PubMed:15084474, PubMed:15471852, PubMed:17582331). Interacts with PRKCG and NTRK1, probably by forming a trimeric complex (PubMed:11418861). Interacts with the Scolopendra mutilans RhTx toxin (By similarity). Interacts with the spider Tau-theraphotoxin-Hs1a (PubMed:27281200). Interacts with TMEM100 (By similarity). Interacts with PACS2 (By similarity). {ECO:0000250|UniProtKB:Q704Y3, ECO:0000250|UniProtKB:Q8NER1, ECO:0000269|PubMed:11418861, ECO:0000269|PubMed:12808128, ECO:0000269|PubMed:15084474, ECO:0000269|PubMed:15190102, ECO:0000269|PubMed:15471852, ECO:0000269|PubMed:23109716, ECO:0000269|PubMed:24305160, ECO:0000269|PubMed:24305161, ECO:0000269|PubMed:27281200}.

Subcellular location: Cell junction, synapse, postsynaptic cell membrane {ECO:0000269|PubMed:15857679}; Multi-pass membrane protein {ECO:0000305}. Cell projection, dendritic spine membrane {ECO:0000269|PubMed:15857679}; Multi-pass membrane protein {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:11578842, ECO:0000269|PubMed:15857679, ECO:0000269|PubMed:9349813}; Multi-pass membrane protein {ECO:0000269|PubMed:24305160, ECO:0000269|PubMed:24305161, ECO:0000269|PubMed:27281200}. Note=Mostly, but not exclusively expressed in postsynaptic dendritic spines. {ECO:0000269|PubMed:15857679}.

Tissue specificity: Predominantly expressed in trigeminal and dorsal root sensory ganglia. Expressed also in hippocampus, cortex, cerebellum, olfactory bulb, mesencephalon and hindbrain. High expression in the cell bodies and dendrites of neurons in the hippocampus and in the cortex. In the brain detected also in astrocytes and pericytes (at protein level) (PubMed:15857679). Isoform 1 and isoform 3 are expressed in brain and peripheral blood mononuclear cells. {ECO:0000269|PubMed:10644739, ECO:0000269|PubMed:15857679, ECO:0000269|PubMed:9349813}.

Domain: The association domain (AD) is necessary for self-association.

Ptm: Phosphorylation by PKA reverses capsaicin-induced dephosphorylation at multiple sites, probably including Ser-116 as a major phosphorylation site. Phosphorylation by CAMKII seems to regulate binding to vanilloids. Phosphorylated and modulated by PRKCE, PRKCM and probably PRKCZ. Dephosphorylation by calcineurin seems to lead to receptor desensitization and phosphorylation by CAMKII recovers activity. {ECO:0000269|PubMed:11884385, ECO:0000269|PubMed:12194871, ECO:0000269|PubMed:14630912, ECO:0000269|PubMed:15471852}.

Miscellaneous: Responses evoked by capsaicin, but not by low pH and heat, can be antagonized by capsazepine.

Miscellaneous: [Isoform 3]: Inactive. {ECO:0000305}.

Similarity: Belongs to the transient receptor (TC 1.A.4) family. TrpV subfamily. TRPV1 sub-subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Rattus norvegicus (Rat).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Rattus.



Function:		Ligand-activated non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli. Seems to mediate proton influx and may be involved in intracellular acidosis in nociceptive neurons. Involved in mediation of inflammatory pain and hyperalgesia. Sensitized by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases, which involves PKC isozymes and PCL. Activation by vanilloids, like capsaicin, and temperatures higher than 42 degrees Celsius, exhibits a time- and Ca(2+)-dependent outward rectification, followed by a long-lasting refractory state. Mild extracellular acidic pH (6.5) potentiates channel activation by noxious heat and vanilloids, whereas acidic conditions (pH <6) directly activate the channel. Can be activated by endogenous compounds, including 12-hydroperoxytetraenoic acid and bradykinin. Acts as ionotropic endocannabinoid receptor with central neuromodulatory effects. Triggers a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamine in the hippocampus and nucleus accumbens by affecting AMPA receptors endocytosis. {ECO:0000269\|PubMed:11140687, ECO:0000269\|PubMed:11418861, ECO:0000269\|PubMed:11578842, ECO:0000269\|PubMed:12095983, ECO:0000269\|PubMed:12194871, ECO:0000269\|PubMed:12764195, ECO:0000269\|PubMed:12808128, ECO:0000269\|PubMed:14523239, ECO:0000269\|PubMed:14630912, ECO:0000269\|PubMed:15173182, ECO:0000269\|PubMed:17582331, ECO:0000269\|PubMed:20510930, ECO:0000269\|PubMed:21076423, ECO:0000269\|PubMed:23109716, ECO:0000269\|PubMed:24305160, ECO:0000269\|PubMed:9349813}.



Function:		[Isoform 3]: Does not display channel activity in response to noxious chemical compounds, such as capsaicin and the vanilloid resiniferatoxin. Channel activity is not elicited by mildly acidic extracellular pH, and only slight channel activity is observed in response to noxiuos heat stimuli. {ECO:0000269\|PubMed:10644739}.


Activity regulation:		Channel activity is activated via the interaction with PIRT and phosphatidylinositol 4,5-bisphosphate (PIP2). Both PIRT and PIP2 are required to activate channel activity (By similarity). The channel is sensitized by ATP binding. Repeated stimulation with capsaicin gives rise to progressively smaller responses, due to desensitization. This desensitization is triggered by the influx of calcium ions and is inhibited by elevated ATP levels. Ca(2+) and CALM displace ATP from its binding site and trigger a conformation change that leads to a closed, desensitized channel. Intracellular PIP2 inhibits desensitization. The double-knot toxin (DkTx) from the Chinese earth tiger tarantula activates the channel and traps it in an open conformation. The Scolopendra mutilans RhTx toxin potentiates the heat activation pathway mediated by this channel by binding to the charge- rich outer pore region (in an activated state) (By similarity). {ECO:0000250, ECO:0000250\|UniProtKB:Q704Y3, ECO:0000269\|PubMed:17582331, ECO:0000269\|PubMed:20510930, ECO:0000269\|PubMed:23109716}.
Subunit:		Interacts with PIRT (By similarity). Homotetramer (PubMed:15190102, PubMed:24305160, PubMed:24305161, PubMed:27281200). May also form a heteromeric channel with TRPV3 (By similarity). Interacts with CALM, PRKCM and CSK (PubMed:12808128, PubMed:15084474, PubMed:15471852, PubMed:17582331). Interacts with PRKCG and NTRK1, probably by forming a trimeric complex (PubMed:11418861). Interacts with the Scolopendra mutilans RhTx toxin (By similarity). Interacts with the spider Tau-theraphotoxin-Hs1a (PubMed:27281200). Interacts with TMEM100 (By similarity). Interacts with PACS2 (By similarity). {ECO:0000250\|UniProtKB:Q704Y3, ECO:0000250\|UniProtKB:Q8NER1, ECO:0000269\|PubMed:11418861, ECO:0000269\|PubMed:12808128, ECO:0000269\|PubMed:15084474, ECO:0000269\|PubMed:15190102, ECO:0000269\|PubMed:15471852, ECO:0000269\|PubMed:23109716, ECO:0000269\|PubMed:24305160, ECO:0000269\|PubMed:24305161, ECO:0000269\|PubMed:27281200}.
Subcellular location:		Cell junction, synapse, postsynaptic cell membrane {ECO:0000269\|PubMed:15857679}; Multi-pass membrane protein {ECO:0000305}. Cell projection, dendritic spine membrane {ECO:0000269\|PubMed:15857679}; Multi-pass membrane protein {ECO:0000305}. Cell membrane {ECO:0000269\|PubMed:11578842, ECO:0000269\|PubMed:15857679, ECO:0000269\|PubMed:9349813}; Multi-pass membrane protein {ECO:0000269\|PubMed:24305160, ECO:0000269\|PubMed:24305161, ECO:0000269\|PubMed:27281200}. Note=Mostly, but not exclusively expressed in postsynaptic dendritic spines. {ECO:0000269\|PubMed:15857679}.
Tissue specificity:		Predominantly expressed in trigeminal and dorsal root sensory ganglia. Expressed also in hippocampus, cortex, cerebellum, olfactory bulb, mesencephalon and hindbrain. High expression in the cell bodies and dendrites of neurons in the hippocampus and in the cortex. In the brain detected also in astrocytes and pericytes (at protein level) (PubMed:15857679). Isoform 1 and isoform 3 are expressed in brain and peripheral blood mononuclear cells. {ECO:0000269\|PubMed:10644739, ECO:0000269\|PubMed:15857679, ECO:0000269\|PubMed:9349813}.
Domain:		The association domain (AD) is necessary for self-association.
Ptm:		Phosphorylation by PKA reverses capsaicin-induced dephosphorylation at multiple sites, probably including Ser-116 as a major phosphorylation site. Phosphorylation by CAMKII seems to regulate binding to vanilloids. Phosphorylated and modulated by PRKCE, PRKCM and probably PRKCZ. Dephosphorylation by calcineurin seems to lead to receptor desensitization and phosphorylation by CAMKII recovers activity. {ECO:0000269\|PubMed:11884385, ECO:0000269\|PubMed:12194871, ECO:0000269\|PubMed:14630912, ECO:0000269\|PubMed:15471852}.
Miscellaneous:		Responses evoked by capsaicin, but not by low pH and heat, can be antagonized by capsazepine.
Miscellaneous:		[Isoform 3]: Inactive. {ECO:0000305}.
Similarity:		Belongs to the transient receptor (TC 1.A.4) family. TrpV subfamily. TRPV1 sub-subfamily. {ECO:0000305}.