TRPC4 as a coincident detector of G and G signaling: mechanisms and pathophysiological implications.

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