Emerging Roles of Diacylglycerol-Sensitive TRPC4/5 Channels

Abstract

Transient receptor potential classical or canonical 4 (TRPC4) and TRPC5 channels are members of the classical or canonical transient receptor potential (TRPC) channel family of non-selective cation channels. TRPC4 and TRPC5 channels are widely accepted as receptor-operated cation channels that are activated in a phospholipase C-dependent manner, following the G_q/11 protein-coupled receptor activation. However, their precise activation mechanism has remained largely elusive for a long time, as the TRPC4 and TRPC5 channels were considered as being insensitive to the second messenger diacylglycerol (DAG) in contrast to the other TRPC channels. Recent findings indicate that the C-terminal interactions with the scaffolding proteins Na⁺/H⁺ exchanger regulatory factor 1 and 2 (NHERF1 and NHERF2) dynamically regulate the DAG sensitivity of the TRPC4 and TRPC5 channels. Interestingly, the C-terminal NHERF binding suppresses, while the dissociation of NHERF enables, the DAG sensitivity of the TRPC4 and TRPC5 channels. This leads to the assumption that all of the TRPC channels are DAG sensitive. The identification of the regulatory function of the NHERF proteins in the TRPC4/5-NHERF protein complex offers a new starting point to get deeper insights into the molecular basis of TRPC channel activation. Future studies will have to unravel the physiological and pathophysiological functions of this multi-protein channel complex.

Keywords: NHERF; TRPC channels; TRPC4; TRPC5; diacylglycerol.

Figure 1

Diacylglycerol (DAG)-mediated activation of transient receptor potential classical or canonical 4/5 (TRPC4/5) channels. Left: Na⁺/H⁺ exchanger regulatory factor (NHERF) proteins and phosphatidylinositol-4,5-bisphosphate (PIP₂) interact with the C-termini of TRPC4/5, which depicts the closed state of the channel. Right: receptor activation (not displayed) leads to the cleavage of PIP₂, resulting in the dissociation of NHERF and in DAG binding, which represents the open state of the channel. Sodium cations (dark green circles), calcium cations (light green circles), and potassium cations (yellow circles) are displayed. The potassium efflux is mainly relevant in the excitable cells.