The PI3K pathway induced by αMSH exerts a negative feedback on melanogenesis and contributes to the release of pigment

Abstract The melanocortin‐1 receptor (MC1R) belongs to the family of the G protein‐coupled receptor (GPCR). Activated GPCRs can promote the phosphoinositide 3‐kinase (PI3K) pathway. Few studies deal with the role of the PI3K pathway activation in response to αMSH. On B16‐F10 cell line, we investigated the αMSH‐dependent modulation of pAKT/AKT, as a key element of the PI3K pathway after rapid and prolonged stimulation. We demonstrated that αMSH triggers a rapid modulation of AKT which culminates in an increase in its phosphorylation. We highlighted a comparable upregulation of pAKT after exposure to αMSH on primary cultures of normal human melanocytes (NHMs) expressing a wild‐type MC1R. On B16‐F10 cells, NHMs, and an ex vivo model of human skin biopsies, we explored the influence of PI3K/AKT signaling triggered by αMSH, focusing on the control of melanogenesis and pigment release. We showed that the αMSH‐dependent PI3K/AKT pathway exerts a negative feedback on melanogenesis and promotes the extracellular release of pigment. We strengthened the role of the PI3K/AKT pathway triggered by αMSH in preserving redox equilibrium and genome integrity, highlighting its role in affecting cell survival.