Inositol-1,4,5-trisphosphate and inositol-1,3,4,5-tetrakisphosphate are second messenger targets for cardioactive neuropeptides encoded on the FMRFamide gene

Debbie Willoughby, Mark S. Yeoman, Paul R. Benjamin

    Research output: Contribution to journalArticlepeer-review


    This paper examines the importance of the calcium-mobilizing inositol phosphate pathway in mediating the effects of FMRFamide and its gene-related neuropeptides on the myogenic heart beat of the pond snail Lymnaea stagnalis. These peptides are encoded on a single exon of the FMRFamide gene and mediate diverse physiological effects in the isolated heart. The rate of production of inositol-l,4,5-trisphosphate [Ins(1,4,5)P3] and inositol-1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4], measured using an HPLC method, were both significantly elevated in a concentration-dependent manner by FMRFamide (and were also elevated by FLRFamide). The threshold for increasing inositol phosphate production was low (100 pmol 1-1) with a peak response occurring at 1 μmol 1-1 FMRFamide. The shape of the dose-response curve for FMRFamide-induced elevation of heart-beat frequency, obtained in pharmacological experiments on the isolated whole heart, was similar to that for stimulation of inositol phosphate levels in homogenized heart tissue. FMRFamide and Ins(1,4,5)P3 produced similar effects on the rate of heart beat in permeabilized whole hearts. In addition, the phospholipase C inhibitor, neomycin (2.5 mmol l-1), blocked the stimulatory effects of FMRFamide on Ins(1,4,5)P3 production in heart homogenate, and attenuated the excitatory effects of this neuropeptide in the isolated heart. The 'isoleucine' pentapeptides, EFLRIamide and pQFYRIamide, also encoded by the FMRFamide gene, produced no significant effects on inositol phosphate production when applied alone or in combination with FMRFamide. These results suggested that FMRFamide (and FLRFamide), but not EFLRIamide and pQFYRIamide, mediated their main effects on heart beat via the inositol phosphate pathway. The fifth peptide, SEQPDVDDYLRDVVLQSEEPLY ('SEEPLY') had no effect when applied alone but appeared to modulate the effects of FMRFamide by delaying the time-to-peak of the Ins(1,4,5)P3 response from 5 s to 20 s by an unknown mechanism.

    Original languageEnglish
    Pages (from-to)2581-2593
    Number of pages13
    JournalJournal of Experimental Biology
    Issue number19
    Publication statusPublished - 1 Jan 1999


    • FMRFamide-related peptide
    • Heart
    • Inositol phosphate
    • Lymnaea stagnalis
    • Multiple peptide signalling


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