TRANSDUCTION MECHANISM OF MOTILIN AND MOTILIDES IN RABBIT DUODENAL SMOOTH-MUSCLE

The present study was undertaken to explore motilin's transduction pat hway in the rabbit, Guanine nucleotides inhibited I-125-motilin bindin g in rabbit antral tissue and increased the dissociation of motilin fr om its receptor. Motilin, the motilin agonist erythromycin A enol ethe r (EM-201) and carbachol (taken as control) increased the production o f inositol phosphates in rabbit duodenal smooth muscle strips labeled with myo-[2-H-3]inositol. The effect of carbachol was blocked by atrop ine, Dose-response curves revealed that 50% of this effect was obtaine d with 3.9 nM motilin, 170 nM EM-201, 0.54 mu M carbachol. Chromatogra phic separation of the inositol phosphate metabolites showed significa nt increases in the levels of [H-3]inositol bisphosphate and of [H-3]i nositol trisphosphate. The three substances were without effect upon t he metabolism of cAMP, nor did they modulate the rise in cAMP induced by GTP. We propose that motilin's transduction pathway uses a G protei n that causes an increase in inositol trisphosphate which is rapidly m etabolized, and which may release calcium from intracellular stores.