TRPC4 as a coincident detector of G_i/o and G_q/11 signaling: mechanisms and pathophysiological implications

TRPC channels are Ca²⁺-permeable nonselective cation channels activated downstream from phospholipase C (PLC). Although most TRPC channels can be activated by stimulating G_q/11-coupled receptors, TRPC4 requires simultaneous stimulation of G_i/o-coupled receptors, making it a perfect detector of coincident G_i/o and G_q/11 signaling. Evidence shows that activated Gα_i/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 G_q/11 proteins. Mechanistically, G_q/11-PLCβ activation produces triggering proton and calcium signals to initiate self-propagating PLCδ1 activity, crucial for G_i/o-mediated TRPC4 function. Thus, TRPC4-containing channels are activated under conditions not only when coincident G_i/o and G_q/11 stimulation occurs, but also when G_i/o stimulation coincides with proton and Ca²⁺ signals. The resulting cytosolic Ca²⁺ rise and membrane depolarization switch the inhibitory G_i/o response to excitation. The conditions and implications of G_i/o-mediated TRPC4 activation in physiology and pathophysiology warrant further investigation.