Nesfatin-1 Suppresses Cardiac L-type Ca2+ Channels Through Melanocortin Type 4 Receptor and the Novel Protein Kinase C Theta Isoform Pathway

摘要: Background/Aims: Nesfatin-1 (NF-1), an anorexic nucleobindin-2 (NUCB2)-derived hypothalamic peptide, acts as a peripheral cardiac modulator and it can induce negative inotropic effects. However, the mechanisms underlying these effects in cardiomyocytes remain unclear. Methods: Using patch clamp, protein kinase assays, western blot analysis, we studied effect of NF-1 on L-type Ca2+ currents (ICa,L) to explore regulatory this adult ventricular myocytes. Results: reversibly decreased ICa,L dose-dependent manner. This was mediated by melanocortin 4 receptor (MC4-R) associated with hyperpolarizing shift voltage-dependence inactivation. Dialysis cells GDP-β-S or anti-Gβ antibody well pertussis toxin pretreatment abolished inhibitory ICa,L. Protein C (PKC) antagonists NF-1-induced responses, whereas inhibition PKA activity intracellular application fast Ca2+-chelator BAPTA elicited no such Application increased membrane abundance PKC theta isoform (PKCθ), PKCθ decrease induced NF-1. Conclusion: These data suggest that suppresses channels via MC4-R couples sequentially βγ subunits Gi/o-protein novel