Stimulation by ghrelin of p42/p44 mitogen-activated protein kinase through the GHS-R1a receptor: role of G-proteins and beta-arrestins.
Results presented in this study indicate that in human embryonic kidney 293 cells (HEK 293), the ghrelin receptor growth hormone secretagogue receptor type 1a (GHS-R1a) activates the extracellular signal-related kinases 1 and 2 (ERK 1/2) via three pathways. One pathway is mediated by the beta-arrestins 1 and 2, and requires entry of the receptor into a multiprotein complex with the beta-arrestins, Src, Raf-1, and ERK 1/2. A second pathway is G(q/11)-dependent and involves a Ca(2+)-dependent PKC (PKCalpha/beta) and Src. A third pathway is G(i)-dependent and involves phosphoinositide 3-kinase (PI3K), PKCepsilon, and Src. Our current study reveals that G(i/o)- and G(q/11)-proteins are crucially involved in the beta-arrestin-mediated ERK 1/2 activation. These results thus support the view that the beta-arrestins act as both scaffolding proteins and signal transducers in ERK 1/2 activation, as reported for other receptors. The different pathways of ERK 1/2 activation suggest that binding to GHS-R1a activates ERK 1/2 pools at different locations within the cell, and thus probably with different physiological consequences.
Camiña
Jesus P
JP
Laboratory of Molecular Endocrinology, Research Area, Complejo Hospitalario Universitario de Santiago (CHUS) and Department of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain. mecamina@usc.es
Lodeiro
Maria
M
Ischenko
Olga
O
Martini
Ana C
AC
Casanueva
Felipe F
FF
D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D019204:GTP-Binding Proteins / Q000378:metabolism; D054439:Ghrelin; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008954:Models, Biological; D036361:Peptide Hormones / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000378:metabolism*; D054440:Receptors, Ghrelin; D000071557:beta-Arrestins
D019390:Arrestins; D054439:Ghrelin; D036361:Peptide Hormones; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D000071557:beta-Arrestins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019204:GTP-Binding Proteins