Abstract
TRPC channels are Ca(2+)-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 Ca(2+) signals. The resulting cytosolic Ca(2+) 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.