Melanocortin receptors mediate α-MSH-induced stimulation of neurite outgrowth in Neuro 2A cells

Abstract

Melanocortins (MC), neuropeptides derived from pro-opiomelanocortin, have been implicated in enhancing neurite outgrowth via an as yet unknown mechanism. Recently, five MC receptors have been identified, three of which, the MC3-R, the MC4-R and the MC5-R, are expressed in the nervous system. In this study, α-MSH and the melanocortin analog [D-Phe7]ACTH (4-10) were able to stimulate neurite outgrowth in the neuroblastoma cell line Neuro 2A. ACTH (4-10), γ2-MSH and ORG2766 were inactive. In addition, the MC4-R antagonist [D-Arg8]ACTH (4-10), inhibited the α-MSH effect, indicating that the MC4-R mediated stimulation of neurite outgrowth by α-MSH. Indeed, the presence of MC4-R mRNA in Neuro 2A cells was demonstrated by a RNase protection assay. Heterologous expression of the MC5-R in Neuro 2A cells lead to the recruitment of a responsiveness to γ2-MSH, but did not increase the effect of α-MSH on neurite outgrowth. This finding indicated that the function of MC4-R can also be exerted by another MC receptor, suggesting that the coupling to G(s), which they have in common, plays an essential role in the neurite outgrowth promoting effect. This was further substantiated by the fact that forskolin treatment per se induced neurite outgrowth in a similar fashion. These data imply that the neurotrophic properties of α-MSH are likely to result from G(s)-coupled MC receptor activity in neuronal cells.