Differential modulation of Ca2(+)-activated K+ channels by substance P

Substance P released from motoneurons or primary afferent nerves innervating the gut is an excitatory noncholinergic regulator of gastrointestinal motility and has been shown to stimulate contractions in longitudinal colonic muscle. By using the patch-clamp technique on single myocytes from the longitudinal muscle of the rabbit colon, we have studied the action of the peptide on membrane conductances. In cell-attached patches, addition of the peptide to the bath activates a large conductance Ca2(+)-activated K+ channel. At peptide concentrations (10(-12) M) that did not result in cell contraction, K+ channels were activated in a synchronized, cyclical fashion. The activation did not occur in the presence of nifedipine (10(-6) M), a blocker of dihydropyridine-sensitive Ca2+ channels. The activation was also absent when the cells were depolarized in 126 mM KCl-Ringer solution. In contrast, at a concentration of the peptide (10(-7) M) that resulted in cell contraction, there was a transient activation of K+ channels, followed by a prolonged inhibition. Nifedipine (10(-6) M) did not block the K+ channel activation by this concentration of the peptide. Removal of bath Ca2+ abolished activation of the K+ channels by both the high and low concentrations of substance P. These results indicate that substance P exerts its effect via two different membrane pathways for extracellular Ca2+.