Signalling mechanism coupled to 5‐hydroxytryptamine4 receptor‐mediated facilitation of fast synaptic transmission in the guinea‐pig ileum myenteric plexus

• Published in: Neurogastroenterology and motility Vol. 15; no. 5; pp. 523 - 529
• Main Authors: Galligan, J. J., Pan, H., Messori, E.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.10.2003
• Subjects: 5‐hydroxytryptamine receptors; Animals; Dose-Response Relationship, Drug; enteric nerves; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - physiology; Guinea Pigs; Ileum - drug effects; Ileum - physiology; In Vitro Techniques; Myenteric Plexus - drug effects; Myenteric Plexus - physiology; protein kinase A; Receptors, Serotonin, 5-HT4 - physiology; Serotonin 5-HT4 Receptor Antagonists; Serotonin Antagonists - pharmacology; Signal Transduction - drug effects; Signal Transduction - physiology; synaptic transmission; Synaptic Transmission - drug effects; Synaptic Transmission - physiology
• ISSN: 1350-1925; 1365-2982
• DOI: 10.1046/j.1365-2982.2003.00428.x

5‐hydroxytryptamine (HT)4 receptor agonists stimulate gastrointestinal motility partly by facilitating acetylcholine release from myenteric neurones. However, the signalling mechanisms that couple 5‐HT4 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‐HT4 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 μg mL−1). Facilitation of fEPSPs caused by renzapride was blocked by the non‐selective protein kinase inhibitors, staurosporine (1 μmol L−1) and H‐8 (30 μmol L−1) and by the selective protein kinase A (PKA) inhibitor, H‐89 (10 μmol L−1). These data indicate that 5‐HT4 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.