Melanocortin-3 receptor activates MAP kinase via PI3 kinase

HEK 293 cells stably expressing human melanocortin-3 receptor (MC3R) were exposed to melanocortin receptor agonist, NDP-MSH (10(-10)-10(-6) M). ERK1/2 was phosphorylated in a dose-dependent manner with an EC50, of 3.3 +/- 1.5 x 10(-9) M, similar to the IC50 of NDP-MSH binding to the MC3R. ERK1/2 phosphorylation was blocked by the melanocortin receptor antagonists SHU9119. NDP-MSH-induced ERKI/2 phosphorylation was sensitive to pertussis toxin and the PI3K inhibitor, wortmannin. Rp-cAMPS, BAPTA-AM and Myr-PKC did not inhibit the NDP-MSH-induced ERKI/2 phosphorylation. NDP-MSH stimulated cellular proliferation in a dose-dependent manner with a similar EC50 to ERKI/2 phosphorylation, 2.1 +/- 0.6 x 10(-9) M. Cellular proliferation was blocked by AGRP (86-132) and by the MEK inhibitor, PD98059. The NDP-MSH did not inhibit serum deprivation-induced apoptosis. MOR activation induces ERKI/2 phosphorylation via PI3K and this pathway is involved in cellular proliferation in HEK cells expressing MOR. (c) 2006 Elsevier B.V. All rights reserved.