文摘
Human RFamide-related peptide-1 (hRFRP-1, MPHSFANLPLRF-NH2) binds to neuropeptide FF receptor 2 (NPFF2R) to dramatically diminish cardiovascular performance. hRFRP-1 and its signaling pathway may provide targets to address cardiac dysfunction. Here, structure鈥揳ctivity relationship, transcript, Ca2+ transient, and phospholabeling data indicate the presence of a hRFRP-1 pathway in cardiomyocytes. Alanyl-substituted and N-terminal truncated analogues identified that R11 was essential for activity, hRFRP-1(8鈥?2) mimicked hRFRP-1, and [A11]hRFRP-1(8鈥?2) antagonized the effect of hRFRP-1 in cellular and integrated cardiac performance. RFRP and NPFF2R transcripts were amplified from cardiomyocytes and heart. Maintenance of the Ca2+ transient when hRFRP-1 impaired myocyte shortening indicated the myofilament was its primary downstream target. Enhanced myofilament protein phosphorylation detected after hRFRP-1 treatment but absent in [A11]hRFRP-1(8鈥?2)-treated cells was consistent with this result. Protein kinase C (PKC) but not PKA inhibitor diminished the influence of hRFRP-1 on the Ca2+ transient. Molecules targeting this pathway may help address cardiovascular disease.