Structure鈥揂ctivity Studies of RFamide-Related Peptide-1 Identify a Functional Receptor Antagonist and Novel Cardiac Myocyte Signaling Pathway Involved in Contractile Performance

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• 作者：Ruthann Nichols ; Chloe Bass ; Leslie Demers ; Brian Larsen ; Elton Li ; Nathan Blewett ; Kimber Converso-Baran ; Mark W. Russell ; Margaret V. Westfall
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7736-7745
• 全文大小：401K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

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.