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 Gq/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.
Highlights
Transient receptor potential classical or canonical 4 (TRPC4) and TRPC5 channels belong to the transient receptor potential classical or canonical (TRPC) cation channel subfamily, which comprises seven members
The first evidence that the TRPC5 channels might be DAG sensitive was presented by Lee and colleagues, who performed electrophysiological whole-cell measurements on murine gastric smooth muscle cells endogenously expressing TRPC5 channels, and found that the channels are activated by OAG [49]
The conformational changes and the kinetics of the conformational changes leading to the TRPC4 and TRPC5 channel activation are largely elusive, as a structure analysis only revealed the inactive channel states
Summary
Transient receptor potential classical or canonical 4 (TRPC4) and TRPC5 channels belong to the transient receptor potential classical or canonical (TRPC) cation channel subfamily, which comprises seven members. TRPC channels are regarded as non-selective, receptor-operated cation channels that are important for calcium homeostasis They are activated via the Gq/11 -signaling cascade as a function of phospholipase C (PLC) [1]. The structural model of TRPC3 reveals two lipid-binding sites, one being sandwiched between the pre-S1 elbow and the S4–S5 linker, and the other being close to the pore-forming domain, where the conserved “LWF” motif of the TRPC family is located [16]. Perhaps these lipid binding sites reflect potential DAG binding sites. NHERF1 and NHERF2 proteins are commonly regarded as adapter proteins that crosslink integral membrane proteins with the cytoskeleton, thereby increasing their membrane localization [46,47,48]
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