BRADYKININ INHIBITS M-CURRENT VIA PHOSPHOLIPASE-C AND CA2-SENSITIVE CA2+ STORES IN RAT SYMPATHETIC NEURONS( RELEASE FROM IP3)

A variety of intracellular signaling pathways can modulate the propert ies 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 su perior cervical ganglion neurons, we find that the signaling pathways underlying M current inhibition by B-2 bradykinin and M-1 muscarinic r eceptors respond very differently to inhibitors. The bradykinin pathwa y was suppressed by the phospholipase C inhibitor U-73122, by blocking the IP3 receptor with pentosan polysulfate or heparin, and by bufferi ng intracellular calcium, and it was occluded by allowing IP3 to diffu se 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 [Ca2+](i) rise with a similar onset a nd time to peak as the inhibition of hi current. The M current inhibit ion and the rise of [Ca2+](i) were blocked by depletion of Ca2+ intern al stores by thapsigargin. We conclude that bradykinin receptors inhib it M current of sympathetic neurons by activating phospholipase C and releasing Ca2+ from IP3-sensitive Ca2+ stores, whereas muscarinic rece ptors do not use the phospholipase C pathway to inhibit hi current cha nnels.