Unsaturated fatty acids prevent desensitization of the human growth hormone secretagogue receptor by blocking its internalization

Abstract

Ghrelin is a metabolically regulated hormone that activates the G protein-coupled receptor GH secretagogue receptor type 1a (GHSR) not only in the pituitary gland but also in peripheral tissues such as the pancreas, stomach, and T cells in the circulation. We have investigated the effects of lipids and altered plasma membrane composition on GHSR activation. Oligounsaturated fatty acids (OFAs) disrupt the structure of membranes and make them more fluid. Prolonged (96 h), but not acute, treatment of the GHSR cells with the 18C OFAs oleic and linoleic acid caused a significant increase in sensitivity of the receptor to ghrelin (EC50 reduced by a factor of 2.4 and 2.9 at 60 and 120 M OFAs, respectively). OFAs were found to block the inhibitory effects of ghrelin pretreatment on subsequent ghrelin responsiveness, suggesting that OFAs suppress desensitization of GHSR. Radioligand displacement studies did not show a significant shift in receptor binding after incubation with OFAs. However, it was found that OFA treatment suppressed GHSR internalization, likely explaining OFA-induced refractoriness to ligand-induced desensitization. The involvement of lipid rafts in this process was indicated by the altered responsiveness of GHSR under conditions that alter membrane cholesterol. In conclusion, our findings demonstrate the importance of membrane composition for GHSR activation and desensitization and indicate at least part of the mechanism through which OFAs and cholesterol could affect ghrelin's activity in vivo.

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

“…This led us to speculate that the anticonvulsant effect of ghrelin may be related to its ability to desensitize the GHSR. It is known that while desensitization and internalization of the GHSR occurs rapidly, resensitization of the receptor to the cell surface is slow [44][45][46]. We found that a 3-minute pretreatment with ghrelin was sufficient for maximal desensitization, and that full resensitization took around 24 h. Also, capromorelin showed anticonvulsant activity combined with strong receptor desensitization potential.…”

Ghrelin receptor activity amplifies hippocampal N‐methyl‐d‐aspartate receptor‐mediated postsynaptic currents and increases phosphorylation of the GluN1 subunit at Ser896 and Ser897

“…One such possibility is the abundance of fatty acids in the in vivo system. Unsaturated fatty acids have been reported to prevent desensitization of human GHSR1a by blocking its internalization (Delhanty et al ., ). In this study, prolonged (96 h), but not acute, treatment of GHSR1a expressing cells in vitro with the 18C oligounsaturated fatty acids (OFAs) oleic and linoleic acid caused a significant increase (by a factor of 2.5–3) in the sensitivity of GHSR1a to ghrelin via a mechanism involving retardation of cellular internalization, rather than altered receptor affinity for the ligand.…”

Ghrelin promotes reorganization of dendritic spines in cultured rat hippocampal slices

“…These signaling pathways are intimately associated with and influenced by cell membrane structure and dynamics including the production of membrane-associated lipids. An exposure of the ghrelin receptor to oleic acid has been reported to delay and inhibit ghrelin-induced desensitization and internalization of the ghrelin receptor [5], suggesting naturally existing unsaturated fatty acids may regulate the ghrelin receptor activity. The production of membrane lipids by the activation of the Gq/11-PLC pathways may have a negative feedback on the desensitization of the ghrelin receptor and maintain continual activation of the receptor until the serum/brain ghrelin level decreases.…”