Ghrelin rapidly elevates protein synthesis in vitro by employing the rpS6K-eEF2K-eEF2 signalling axis

Activated ghrelin receptor GHS-R1 alpha triggers cell signalling pathways that modulate energy homeostasis and biosynthetic processes. However, the effects of ghrelin on mRNA translation are unknown. Using various reporter assays, here we demonstrate a rapid elevation of protein synthesis in cells within 15-30 min upon stimulation of GHS-R1 alpha by ghrelin. We further show that ghrelin-induced activation of translation is mediated, at least in part, through the de-phosphorylation (de-suppression) of elongation factor 2 (eEF2). The levels of eEF2 phosphorylation at Thr56 decrease due to the reduced activity of eEF2 kinase, which is inhibited via Ser366 phosphorylation by rpS6 kinases. Being stress-susceptible, the ghrelin-mediated decrease in eEF2 phosphorylation can be abolished by glucose deprivation and mitochondrial uncoupling. We believe that the observed burst of translation benefits rapid restocking of neuropeptides, which are released upon GHS-R1a activation, and represents the most time- and energy-efficient way of prompt recharging the orexigenic neuronal circuitry.

Automated summary

Activated ghrelin receptor GHS-R1 alpha regulates energy homeostasis and biosynthetic processes. New research shows that ghrelin can rapidly enhance protein synthesis in cells by dephosphorylating eEF2. This translation activation process may contribute to the rapid replenishment of neuropeptides released upon GHS-R1a activation.