Selective G?i subunits as novel direct activators of transient receptor potential canonical (TRPC)4 and TRPC5 channels.

ABSTRACT: The ubiquitous transient receptor potential canonical (TRPC) channels function as non-selective, Ca(2+)-permeable channels and mediate numerous cellular functions. It is commonly assumed that TRPC channels are activated by stimulation of G?(q)-PLC-coupled receptors. However, whether the G?(q)-PLC pathway is the main regulator of TRPC4/5 channels and how other G? proteins may regulate these channels are poorly understood. We previously reported that TRPC4/TRPC5 can be activated by G?(i). In the current work, we found that G?(i) subunits, rather than G?(q), are the primary and direct activators of TRPC4 and TRPC5. We report a novel molecular mechanism in which TRPC4 is activated by several G?(i) subunits, most prominently by G?(i2), and TRPC5 is activated primarily by G?(i3). Activation of G?(i) by the muscarinic M2 receptors or expression of the constitutively active G?(i) mutants equally and fully activates the channels. Moreover, both TRPC4 and TRPC5 are activated by direct interaction of their conserved C-terminal SESTD (SEC14-like and spectrin-type domains) with the G?(i) subunits. Two amino acids (lysine 715 and arginine 716) of the TRPC4 C terminus were identified by structural modeling as mediating the interaction with G?(i2). These findings indicate an essential role of G?(i) proteins as novel activators for TRPC4/5 and reveal the molecular mechanism by which G-proteins activate the channels.

SUBMITTER: Jeon JP 

PROVIDER: S-EPMC3366817 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature