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Volume 17, Number 3, Issue of February 1, 1997 pp. 1011-1024
Copyright ©1997 Society for Neuroscience

Mediation by Protein Kinases C and A of Go-Linked Slow Responses of Enteric Neurons to 5-HT

Received July 3, 1996; revised Oct. 21, 1996; accepted Nov. 22, 1996.

Hui Pan1, Hoau-Yan Wang2, Eitan Friedman2, and Michael D. Gershon1

1 Department of Anatomy and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York 10032, and 2 Department of Pharmacology, Allegheny University of the Health Sciences, MCP-Hahnemann School of Medicine, Philadelphia, Pennsylvania 19129

5-HT activates the peristaltic reflex and is the neurotransmitter of a subset of myenteric interneurons. Hyperpolarizing afterpotential (AH)/type 2 neurons respond to 5-HT with a long-lived depolarization that is caused by the inhibition of a Ca2+-activated K+ conductance (gKCa). This effect is mediated by a G-protein-coupled receptor, 5-HT1P. 5-HT1P agonists specifically activate Galpha o, the immunoreactivity of which was found to be highly abundant and membrane-associated in almost all enteric neurons. Responses of hyperpolarizing AH/type 2 neurons to 5-HT were inhibited by intracellular injection of GDPbeta S or anti-Galpha o Fab fragments but were potentiated and prolonged by intracellular GTPgamma S. Responses to 5-HT were antagonized by pertussis toxin, downregulation of protein kinase C (PKC) and inhibitors of phosphatidylcholine phospholipase C (PC-PLC), PKC (including pseudosubstrate peptides, chelerythrine, and the alpha /beta isoform-specific inhibitor Gö 6976), protein kinase A (PKA), and adenylate cyclase. Responses to 5-HT were mimicked by activators of PKC, and 5-HT induced a concentration-dependent increase in the membrane-associated PKC activity in isolated myenteric ganglia. Immunocytochemical studies suggested that the most abundant isoforms of PKC in enteric neurons are alpha  and delta . These data suggest that signal transduction of the 5-HT1P-mediated slow response to 5-HT involves activation of PC-PLC by Galpha o to liberate diacylglycerol, which stimulates PKC (most likely alpha ). PKC probably activates adenylate cyclase, which through cAMP, activates PKA. Activation of both PKA and PKC lead to closure of gKCa.

Key words: enteric nervous system; serotonin; 5-hydroxytryptamine; 5-HT1P receptor; protein kinase C; protein kinase A; phosphatidylcholine phospholipase C; Go; G-proteins; signal transduction




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