Optimization of Ghrelin receptor bias modulators for the treatment of addictive disorders

Authors

• K Afratis
• D Kim
• JD Gross
• L Barak
• X Hu
• N Southall
• M Ferrer
• J Marugan

Abstract

Ghrelin is a peptide hormone produced mainly by the oxyntic glands in the stomach and it is known as the “hunger hormone” as its regulation is associated with food intake and metabolism. Ghrelin is the endogenous ligand for the G-Protein coupled receptor (GPCR): GHSR1a (Growth Hormone Secretagogue Receptor 1a).
G-Protein Coupled Receptors (GPCRs) contain seven-transmembrane domains that are coupled with heterotrimeric G proteins containing three different subunits (α, β, γ). G proteins are activated by signal-receptor interactions on the cell’s surface with ligands which leads to the synthesis of secondary messengers. When the GPCR is phosphorylated by GRK, then β-arrestin binds and lead to different cellular responses from G-protein signaling, including desensitization and internalization. (Figure 1). Henceforth, GHSR1a cellular responses are dependent on each pathway that is selectively activated. Based on its distinct signaling pathways, the GHSR1a can educe different physiological responses which represents a promising strategy for targeting diseases by modulating biased signaling pathways over others (Figure 1). GHSR1a is greatly expressed in the central nervous system (CNS) and has been shown to modulate dopamine (DA) homeostasis and offers anticonvulsant and neuroprotective effects, however, its activity in the CNS is less defined. Our target is to develop biased G-protein signaling GHSR1a agonists and investigate their effect on regulation of DA homeostasis and addictive disorders

Scientific Focus Area: Chemical Biology

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