Dynamic NHERF interaction with TRPC4/5 proteins is required for channel gating by diacylglycerol

This is the authors' abstract. We don't add key points for this paper.

Significance Transient receptor potential cation (TRPC) 4 and 5 channels are nonselective cation channels activated via G protein-coupled receptors. In contrast to all other TRPC channels, they are regarded as insensitive to the phospholipase C (PLC) product diacylglycerol (DAG). Deeper insight into the G protein-dependent activation mechanism of TRPC4/5 channels is lacking. In this study we unravel the G q/11 protein-mediated signaling pathway leading to TRPC4/5 activation. Depletion of phosphatidylinositol 4,5-bisphosphate causes a conformational change of the TRPC5 C terminus leading to dissociation of Na + /H + exchanger regulatory factor (NHERF) proteins thereby inducing a DAG-sensitive channel state. Our findings reveal a previously unidentified activation mechanism of TRPC4/5 channels with NHERF proteins as dynamic regulators of channel activity. Moreover, we demonstrate that TRPC channels are DAG sensitive.