TRPC5: A Startling Discovery

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