Stimulation by ghrelin of p42/p44 nitogen-activated protein kinase through the GHS-R1a receptor:: Role of g-proteins and β-arrestins

Results presented in this study indicate that in human embryonic kidney 293 cells (HEK 293), the ghrelin receptor growth hormone secretagogue receptor type 1 a (GHS-R1a) activates the extracellular signal-related kinases 1 and 2 (ERK1/2) 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 ERK1/2. A second pathway is G(q/11)-dependent and involves a Ca2+-dependent PKC (PKC alpha/beta) and Src. A third pathway is G(i)-dependent and involves phosphoinositide 3-kinase (PI3K), PKC epsilon, and Src. Our current study reveals that G(i/o) and G(q/11)-proteins are crucially involved in the P-arrestin-mediated ERK1/2 activation. These results thus support the view that the beta-arrestins act as both scaffolding proteins and signal transducers in ERK1/2 activation, as reported for other receptors. The different pathways of ERK1/2 activation suggest that binding to GHS-R1a activates ERK1/2 pools at different locations within the cell, and thus probably with different physiological consequences.