Bradykinin inhibits M current via phospholipase C and Ca(2+) release from IP(3)-sensitive Ca(2+) stores in rat sympathetic neurons

A variety of intracellular signaling pathways can modulate the properties of voltage-gated ion channels. Some of them are well characterized. However, the diffusible second messenger mediating suppression of M current via G protein-coupled receptors has not been identified. In superior cervical ganglion neurons, we find that the signaling pathways underlying M current inhibition by B(2) bradykinin and M(1) muscarinic receptors respond very differently to inhibitors. The bradykinin pathway was suppressed by the phospholipase C inhibitor U-73122, by blocking the IP(3) receptor with pentosan polysulfate or heparin, and by buffering intracellular calcium, and it was occluded by allowing IP(3) to diffuse into the cytoplasm via a patch pipette. By contrast, the muscarinic pathway was not disrupted by any of these treatments. The addition of bradykinin was accompanied by a [Ca(2+)](i) rise with a similar onset and time to peak as the inhibition of M current. The M current inhibition and the rise of [Ca(2+)](i) were blocked by depletion of Ca(2+) internal stores by thapsigargin. We conclude that bradykinin receptors inhibit M current of sympathetic neurons by activating phospholipase C and releasing Ca(2+) from IP(3)-sensitive Ca(2+) stores, whereas muscarinic receptors do not use the phospholipase C pathway to inhibit M current channels.