Signalling mechanism coupled to 5-hydroxytryptamine[sub 4] receptor-mediated facilitation of fast synaptic transmission in the guinea-pig ileum myenteric plexus.

Abstract 5-hydroxytryptamine (HT)[sub 4] receptor agonists stimulate gastrointestinal motility partly by facilitating acetylcholine release from myenteric neurones. However, the signalling mechanisms that couple 5-HT[sub 4] receptor activation to increased transmitter release in the myenteric plexus are unknown. We used conventional intracellular electrophysiological methods to record fast excitatory postsynaptic potentials (fEPSPs) from neurones in the guinea-pig ileum myenteric plexus preparation. The substituted benzamide, renzapride, acted at 5-HT[sub 4] receptors to facilitate fEPSPs. This response was mimicked by forskolin, an activator of adenylate cyclase. Facilitation of fEPSPs by renzapride and forskolin was not blocked by treating tissues with pertussis toxin (PTX) (2 h, 2 μ g mL[sup -1] ). Facilitation of fEPSPs caused by renzapride was blocked by the non-selective protein kinase inhibitors, staurosporine (1 μ mol L[sup -1] ) and H-8 (30 μ mol L[sup -1] ) and by the selective protein kinase A (PKA) inhibitor, H-89 (10 μ mol L[sup -1] ). These data indicate that 5-HT[sub 4] receptors act via a PTX-resistant mechanism to activate PKA. Protein kinase A activation leads to an increase in transmitter release from myenteric nerve terminals and a facilitation of fast excitatory synaptic transmission. [ABSTRACT FROM AUTHOR]