title: Melanocortin 5 receptor signaling and internalization: role of MAPK/ERK pathway and β-arrestins 1/2.
abstract: The Melanocortin 5 receptor (MC5R) is a G-protein coupled receptor (GPCR) that exhibits high affinity for α-MSH. Here we present evidence for MC5R-GFP internalization and subsequent recycling to cell surface, in α-MSH-stimulated HeLa cells. This melanocortin induces a biphasic activation of ERK1/2 with an early peak at 15min, a G(i)-protein driven, β-arrestins 1/2 independent process, and a late sustained activation that is regulated by β-arrestins 1/2. ERK1/2 lead to downstream phosphorylation of 90-kDa ribosomal S6 kinases (p90RSK) and mitogen- and stress-activated protein kinase 1 (MSK1). Only a small fraction (10%) of phosphorylated p90RSK and ERK1/2 translocates to the nucleus inducing c-Fos expression. α-MSH also activates CREB through cAMP/PKA pathway. In 3T3-L1 adipocytes, where MC5R is endogenously expressed, α-MSH also induces phosphorylation and cytosolic retention of the same signaling molecules. These findings provide new evidence on the signaling mechanisms underlying MC5R biological response to α-MSH.
authors.affiliation: Department of Experimental Biology, Faculty of Medicine, Universidade do Porto, Porto, Portugal.
authors.forename: Adriana R
authors.initials: AR
authors.lastname: Rodrigues
authors.forename: Henrique
authors.initials: H
authors.lastname: Almeida
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Gouveia
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000201:enzymology; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004705:Endocytosis; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D020868:Gene Silencing; D005799:Genes, Dominant; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D044101:Receptors, Melanocortin / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D034741:RNA, Small Interfering; D044101:Receptors, Melanocortin; D000071557:beta-Arrestins; C086971:melanocortin 5 receptor; D049452:Green Fluorescent Proteins; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D019204:GTP-Binding Proteins