PHARMACOLOGY OF CARDIOEXCITATORY NEUROPEPTIDES

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FMRFamide (Phe-Met-Arg-Phe-NH2) is a neuropeptide isolated from clam ganglia; it is stored in granules, and released upon depolarization. FMRFamide is a potent molluscan pharmacon: it is cardioexcitatory or inhibitory depending on species; it causes contractures of various muscles and affects neuronal activity. FMRFamide is only one example of a set of heterogenous, but structurally and functionally homologous, molluscan neuropeptides. Moreover, it is hypothesized that FMRFamide-like peptides are widely distributed among animals, including vertebrates, and may have had a common origin with the opioid peptides in protein evolution. This project focuses on the phyletic distribution and mechanisms of action of FMRFamide. First, three peptides, already identified in the brains of the gastropods, Busycon contrarium and Helix aspersa, will be further purified by high performance liquid chromatography, and their amino acid compositions and sequences determined. The extraction and purification steps will be monitored by bioassays specific for FMRFamide (Busycon radula protactor muscle) or of the opioid peptides (guinea-pig ileum and mouse vas deferens). FMRFamide-like peptides will also be sought in other tissues: porcine adrenal medulla and sympathetic ganglia; and the central ganglia from other invertebrate phyla. As these peptides are characterized, their subcellular localization will be determined, and their release by potassium depolarization will be demonstrated. A particle-bound peptidase, coverting N-terminal extended precursors to FMRFamide, has been proposed; an attempt will be made to demonstrate it. FMRFamide receptors will be characterized by structure-activity studies on particular molluscan hearts and muscles and on rabbit vascular smooth muscle; the selected preparations are sensitive to the peptide; and their responses exemplify the range of its effects. The inotropic effects of FMRFamide will be correlated with its actions on cyclic nucleotide levels. The sucrose gap technique will be used to correlate electrical and mechanical responses.