Stimulation by ghrelin of p42/p44 mitogen‐activated protein kinase through the GHS‐R1a receptor: Role of G‐proteins and β‐arrestins

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Abstract
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 β‐arrestins 1 and 2, and requires entry of the receptor into a multiprotein complex with the β‐arrestins, Src, Raf‐1, and ERK 1/2. A second pathway is Gq/11‐dependent and involves a Ca2+‐dependent PKC (PKCα/β) and Src. A third pathway is Gi‐dependent and involves phosphoinositide 3‐kinase (PI3K), PKCε, and Src. Our current study reveals that Gi/o‐ and Gq/11‐proteins are crucially involved in the β‐arrestin‐mediated ERK 1/2 activation. These results thus support the view that the β‐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. J. Cell. Physiol. 213: 187–200, 2007.