MRAP2 inhibits β-arrestin recruitment to the ghrelin receptor by preventing GHSR1a phosphorylation

Area of Science:

• Endocrinology
• Molecular Pharmacology
• G protein-coupled receptor signaling

Background:

• Melanocortin receptor accessory protein 2 (MRAP2) is crucial for growth hormone secretagogue receptor 1a (GHSR1a) function, influencing appetite and insulin secretion.
• GHSR1a exhibits distinct signaling patterns with and without MRAP2, including constitutive activity and differential β-arrestin recruitment.

Purpose of the Study:

• To elucidate the mechanism by which MRAP2 modifies GHSR1a signaling.
• To investigate the role of specific GHSR1a phosphorylation sites in β-arrestin recruitment.
• To understand MRAP2's effect on GHSR1a phosphorylation and its interaction with β-arrestin.

Main Methods:

• Investigated phosphorylation sites in the C-terminal tail and third intracellular loop of GHSR1a.
• Assessed the impact of MRAP2 on GHSR1a's interaction with β-arrestin.
• Examined the influence of MRAP2 on the phosphorylation of GHSR1a by GRK2 and PKC.

Main Results:

• Serine 252 and Threonine 261 in GHSR1a's third intracellular loop are key for β-arrestin recruitment.
• The C-terminal region of GHSR1a is not essential for β-arrestin interaction.
• MRAP2 inhibits GHSR1a phosphorylation by preventing GRK2 and PKC binding to the receptor.

Conclusions:

• MRAP2 alters GHSR1a signaling by directly modulating the receptor's phosphorylation state.
• The C-terminal tail of GHSR1a appears to inhibit, rather than facilitate, β-arrestin recruitment.
• MRAP2 plays a significant role in fine-tuning GHSR1a-mediated physiological responses.