Regulation of ERK1/2 activity by ghrelin‐activated growth hormone secretagogue receptor 1A involves a PLC/PKCɛ pathway

Open Access
Publisher Website
Google Scholar
Abstract
The growth hormone secretagogue receptor 1a (GHSR‐1a) is a G‐protein coupled receptor, involved in the biological actions of ghrelin by triggering inositol phosphates and calcium intracellular second messengers. It has also been reported that ghrelin could activate the 44‐ and 42‐kDa extracellular signal‐regulated protein kinases (ERK1/2) in different cell lines, but it is not clear whether this regulation is GHSR‐1a dependent or not. To provide direct evidence for the coupling of GHSR‐1a to ERK1/2 activation, this pathway has been studied in a heterologous expression system. Thus, in Chinese hamster ovary (CHO) cells we showed that ghrelin induced, via the human GHSR‐1a, a transient and dose‐dependent activation of ERK1/2 leading to activation of the transcriptional factor Elk1. We then investigated the precise mechanisms involved in GHSR‐1a‐mediated ERK1/2 activation using various specific inhibitors and dominant‐negative mutants and found that internalization of GHSR‐1a was not necessary. Our results also indicate that phospholipase C (PLC) was involved in GHSR‐1a‐mediated ERK1/2 activation, however, pathways like tyrosine kinases, including Src, and phosphoinositide 3‐kinases were not found to be involved. GHSR‐1a‐mediated ERK1/2 activation was abolished both by a general protein kinase C (PKC) inhibitor, Gö6983, and by PKC depletion using overnight pretreatment with phorbol ester. Moreover, the calcium chelator, BAPTA‐AM, and the inhibitor of conventional PKCs, Gö6976, had no effect on the GHSR‐1a‐mediated ERK1/2 activation, suggesting the involvement of novel PKC isoforms (ɛ, δ), but not conventional or atypical PKCs. Further analyses suggest that PKCɛ is required for the activation of ERK1/2. Taken together, these data suggest that ghrelin, through GHSR‐1a, activates the Elk1 transcriptional factor and ERK1/2 by a PLC‐ and PKCɛ‐dependent pathway. British Journal of Pharmacology (2006) 148, 350–365. doi:10.1038/sj.bjp.0706727

This publication has 88 references indexed in Scilit: