SIGNAL-TRANSDUCTION PATHWAYS CAUSING SLOW SYNAPTIC EXCITATION IN GUINEA-PIG MYENTERIC AH NEURONS

Intracellular recordings were obtained from myenteric AH neurons of guinea pig ileum in vitro. Slow excitatory synaptic responses associated with decreased potassium conductance (g(K)), inhibition of the spike afterhyperpolarization current (AHC), and increased chloride conductance (g(Cl)) were mimicked by senktide, a neurokinins receptor agonist. Intracellular guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) decreased g(K) and increased gel irreversibly after nerve stimulation or senktide application. Myenteric neurons in pertussis toxin (PTX)-treated tissues responded normally to senktide and nerve stimulation. Forskolin and phorbol 12,13-dibutyrate (PDBu) inhibited g(K) and the AHC but did not activate g(Cl). The AHC was not reduced by subthreshold concentrations of forskolin (10 nM) or PDBu (3 nM) alone but was inhibited by forskolin and PDBu applied together. Inhibitors of phospholipase C (D-609) or protein kinases (staurosporine) reduced slow synaptic and senktide responses. The protein phosphatase inhibitor, calyculin A, caused an inward current, a decrease in g(K), and AHC inhibition but did not activate g(Cl) We conclude that slow excitatory synaptic responses are mediated by PTX-insensitive G proteins and activation of phospholipase C and protein kinases. Forskolin and PDBu activate pathways that inhibit g(K) The mechanisms for activation of g(Cl) are unknown.