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

This paper examines the importance of the calcium-mobilizing inositol phosp hate pathway in mediating the effects of FMRFamide and its gene-related neu ropeptides on the myogenic heart beat of the pond snail Lymnaea stagnalis, These peptides are encoded on a single exon of the FMRFamide gene and media te diverse physiological effects in the isolated heart. The rate of product ion of inositol-1,4,5-trisphosphate [Ins(1,4,5)P-3] and inositol-1,3,4,5-te trakisphosphate [Ins(1,3,4,5)P-4], measured using an HPLC method, were both significantly elevated in a concentration-dependent manner by FMRFamide (a nd were also elevated by FLRFamide. The threshold for increasing inositol p hosphate production was low (100 pmol l(-1)) with a peak response occurring at 1 mu mol l(-1) FMRFamide, The shape of the dose-response curve for FMRF amide-induced elevation of heart-beat frequency, obtained in pharmacologica l experiments on the isolated whole heart, was similar to that for stimulat ion of inositol phosphate levels in homogenized heart tissue, FMRFamide and Ins(1,4,5)P-3 produced similar effects on the rate of heart beat in permea bilized whole hearts, In the phospholipase C inhibitor, neomycin (2.5 mmol l(-1)), blocked the stimulatory effects of FMRFamide on Ins(1,4,5)P-3 produ ction in heart homogenate, and attenuated the excitatory effects of this ne uropeptide in the isolated heart, The 'isoleucine' pentapeptides, EFLRIamid e and pQFYRIamide, also encoded by the FMRFamide gene, produced no signific ant effects on inositol phosphate production when applied alone or in combi nation with FMRFamide, These results suggested that FMRFamide land FLRFamid e), but not EFLRIamide and pQFYRIamide, mediated their main effects on hear t beat via the inositol phosphate pathway. The fifth peptide, SEQPDVDDYLRDV VLQSEEPLY ('SEEPLY') had no effect when applied alone but appeared to modul ate the effects of FMRFamide by delaying the time-to-peak of the Ins(1,4,5) P-3 response from 5 s to 20 s by an unknown mechanism.