TRPC channels are Ca2+-permeable nonselective cation channels activated downstream from phospholipase C (PLC). Although most TRPC channels can be activated by stimulating Gq/11-coupled receptors, TRPC4 requires simultaneous stimulation of Gi/o-coupled receptors, making it a perfect detector of coincident Gi/o and Gq/11 signaling. Evidence shows that activated Gαi/o proteins work together with PLCδ1 to induce robust TRPC4 activation and the process is accelerated by stimulation of other PLC isozymes, such as PLCβ through Gq/11 proteins. Mechanistically, Gq/11-PLCβ activation produces triggering proton and calcium signals to initiate self-propagating PLCδ1 activity, crucial for Gi/o-mediated TRPC4 function. Thus, TRPC4-containing channels are activated under conditions not only when coincident Gi/o and Gq/11 stimulation occurs, but also when Gi/o stimulation coincides with proton and Ca2+ signals. The resulting cytosolic Ca2+ rise and membrane depolarization switch the inhibitory Gi/o response to excitation. The conditions and implications of Gi/o-mediated TRPC4 activation in physiology and pathophysiology warrant further investigation.
Keywords: GPCR; TRP channels; acidosis; calcium signaling; heterotrimeric G proteins; phospholipase C.