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. Author manuscript; available in PMC: 2015 Oct 2.
Published in final edited form as: Nature. 2015 Jan 19;520(7545):94–98. doi: 10.1038/nature14051

Fig. 4. Biased agonists of the MC4R support a role for Kir7.1 in melanocortin signaling in vivo.

Fig. 4

a, The potencies of wtAgRP (83-132, IC50, 9.9e-008) and miniAgRP (87-122, IC50, 1.0e-007) for inhibition of MC4R constitutive activity, measured by applying AgRPs indicated are not significantly different (p>0.1). b, Potencies of wtAgRP (3.6e-009) and miniAgRP (1.7e-007) are significantly different for stimulation of Kir7.1 activity. c–d, The α-MSH analogue MC4-NN2-0453 (Novo) is a biased agonist for coupling of the MC4R to Kir7.1. Coupling to intracellular cAMP: (Novo EC50 = 4.9×10−9 M; LY EC50 = 41.6×10−10 M;), Coupling to inhibition of thallium flux through Kir7.1 (Novo EC50 = 4.5×10−10 M; LY EC50 = 4.1×10−9 M; α-MSH EC50 = 1.6×10−8 M). e–f, Application of Novo induced significant depolarization of membrane potential in PVN neurons. g, ip administration of LY stimulated PYY release from L cells in vivo via an MC4R-dependent pathway, while NOVO did not. Data show mean and sem, ***p<0.001. (h) Novo is a potent inhibitor of cumulative food intake, following an overnight fast and administration of equimolar doses of compounds indicated (6.9 mg/kg Novo or 3 mg/kg LY) Data show mean +/− SEM, *p<0.05; **p<0.01, ***p<0.001, by paired t test (e), or 1-way ANOVA with Bonferroni post-test (g&h).