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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. Activated by vanilloids, like capsaicin, and temperatures higher than 42 degrees Celsius (PubMed:37117175). Upon activation, 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"}],"commentType":"FUNCTION"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"Ca(2+)(in) = Ca(2+)(out)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:29671"},{"database":"ChEBI","id":"CHEBI:29108"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11050376"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11226139"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12077606"}]}},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"Mg(2+)(in) = Mg(2+)(out)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:29827"},{"database":"ChEBI","id":"CHEBI:18420"}],"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O35433"}]}},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"Na(+)(in) = Na(+)(out)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:34963"},{"database":"ChEBI","id":"CHEBI:29101"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37117175"}]}},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"K(+)(in) = K(+)(out)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:29463"},{"database":"ChEBI","id":"CHEBI:29103"}],"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O35433"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O35433"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q704Y3"}],"value":"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 (By similarity). 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)"}],"commentType":"ACTIVITY REGULATION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O35433"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q704Y3"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12077606"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29656858"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37117175"}],"value":"Homotetramer (PubMed:37117175). Interacts with PIRT (By similarity). Interacts with TRPV3 and may also form a heteromeric channel with TRPV3 (PubMed:12077606). Interacts with CALM, PRKCM and CSK. Interacts with PRKCG and NTRK1, probably by forming a trimeric complex (By similarity). Interacts with the Scolopendra mutilans RhTx toxin (By similarity). Interacts with TMEM100 (By similarity). Interacts with PACS2 (PubMed:29656858)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O35433"}],"value":"Mostly, but not exclusively expressed in postsynaptic dendritic spines"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O35433"}],"value":"Postsynaptic cell membrane","id":"SL-0219"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37117175"}],"value":"Multi-pass membrane protein","id":"SL-9909"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O35433"}],"value":"Cell projection, dendritic spine membrane","id":"SL-0285"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37117175"}],"value":"Multi-pass membrane protein","id":"SL-9909"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11050376"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11243859"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12077606"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37117175"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37117175"}],"value":"Multi-pass membrane protein","id":"SL-9909"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"1"},"isoformIds":["Q8NER1-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"2"},"isoformIds":["Q8NER1-3"],"sequenceIds":["VSP_056862"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11050376"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11243859"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14987252"}],"value":"Widely expressed at low levels. Expression is elevated in dorsal root ganglia. In skin, expressed in cutaneous sensory nerve fibers, mast cells, epidermal keratinocytes, dermal blood vessels, the inner root sheet and the infundibulum of hair follicles, differentiated sebocytes, sweat gland ducts, and the secretory portion of eccrine sweat glands (at protein level)"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O35433"}],"value":"The association domain (AD) is necessary for self-association"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O35433"}],"value":"Phosphorylation by PKA reverses capsaicin-induced dephosphorylation at multiple sites, probably including Ser-117 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"}],"commentType":"PTM"},{"texts":[{"value":"Responses evoked by low pH and heat, and capsaicin can be antagonized by capsazepine"}],"commentType":"MISCELLANEOUS"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the transient receptor (TC 1.A.4) family. TrpV subfamily. 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