Receptor-mediated regulation of the nonselective cation channels TRPC4 andTRPC5

Mammalian transient receptor potential channels (TRPCs) form a family of Ca 2+-permeable cation channels currently consisting of seven members, TRPC1-T RPC7. These channels have been proposed to be molecular correlates for capa citative Ca2+ entry channels. There are only a few studies on the regulatio n and properties of the subfamily consisting of TRPC4 and TRPC5, and there are contradictory reports concerning the possible role of intracellular Ca2 + store depletion in channel activation. We therefore investigated the regu latory and biophysical properties of murine TRPC4 and TRPC5 (mTRPC4/5) hete rologously expressed in human embryonic kidney cells. Activation of G(q/11) -coupled receptors or receptor tyrosine kinases induced Mn2+ entry in fura- 2-loaded mTRPC4/5-expressing cells. Accordingly, in whole-cell recordings, stimulation of G(q/11)-coupled receptors evoked large, nonselective cation currents, an effect mimicked by infusion of guanosine 5'-3-O-(thio)triphosp hate (GTP gamma S). However, depletion of intracellular Ca2+ stores failed to activate mTRPC4/5, In inside-out patches, single channels with conductan ces of 42 and 66 picosiemens at -60 mV for mTRPC4 and mTRPC5, respectively, were stimulated by GTP gamma S in a membrane-confined manner. Thus, mTRPC4 and mTRPC5 form nonselective cation channels that integrate signaling path ways from G-protein-coupled receptors and receptor tyrosine kinases indepen dently of store depletion. Furthermore, the biophysical properties of mTRPC 4/5 are inconsistent with those of I-crac the most extensively characterize d store-operated current.