Fig. 6.

Signaling mechanisms of melanocortin 5 receptor (MC5R). MC5R activates two parallel signaling pathways, Gs/cAMP/PKA and Gi/PI3K/ERK1/2 that promote CREB phosphorylation and c-fos expression, respectively. MC5R is also known to increase intracellular Ca²⁺ levels and promote JAK/STAT activation. ERK1/2 signaling occurs through a biphasic fashion with an early transient peak dependent from Gi protein and a second one, more sustained in time, regulated by Gi and β-arrestins. MC5R internalizes independently from β-arrestins but these scaffold molecules seem to retain ERK1/2 signaling in the cytoplasm to mediate MC5R-dependent decrease of fatty acid re-esterification in adipocytes. MC5R-dependent increase of lipolysis rate is regulated by PKA activation