TRPC5, a protein of the canonical transient receptor potential ion channel family, is primarily found in themammalian central nervous system. Heterologous expression of TRPC5 indicates that it forms a non-selective cationchannel functioning downstream of G-protein coupled receptor (GPCR) activation, with substantial sensitivity tointracellular calcium. TRPC5 can form a related heteromeric channel with TRPC1, also controlled by GPCRs andcalcium, but with unique biophysical properties. Pharmacology for TRPC5 is minimal; the only small molecules known toactivate (lanthanides) and block (2-APB, SKF96365, and flufenamate) the channel are non-specific. In vivo and ex vivostudies have validated several roles for TRPC5 in mammals. Multiple reports implicate TRPC5 in neuronal processextension, suggesting that it could be a target for central nervous system regenerative therapies in spinal cord or braininjury. TRPC5 knockout mice exhibit reduced innate fear, making TRPC5 a candidate for the development of novelanxiolytics. While less validated, several preliminary studies suggest additional roles for TRPC5. Gonadotropin releasinghormone neurons express TRPC5 and respond to native peptide activation with a TRPC5-like current, raising thepossibility for modulation of existing gonadotropin based therapies for infertility and hypogonadism. TRPC5 proteinlevels are elevated in a porcine model of metabolic syndrome, and may play a role in hypertension and cardiovasculardisease. TRPC5 is likely expressed in trigeminal neurons, and may function in sensation. Debate continues over theinvolvement of TRPC5 in store-operated calcium entry, a cellular process necessary for T cell activation and the functionsof many cell types.
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