Melanocortin-4 Receptor PLC Activation Is Modulated by an Interaction with the Monocarboxylate Transporter 8

Area of Science:

• Neuroendocrinology
• Molecular Endocrinology
• GPCR Signaling

Background:

• The melanocortin-4 receptor (MC4R) is crucial for regulating appetite and energy balance via the hypothalamic leptin pathway.
• G protein-coupled receptors (GPCRs), including MC4R, can form heterodimers with other membrane proteins, influencing their function.
• Thyroid hormones (TH) are vital for energy homeostasis, and their transport is mediated by monocarboxylate transporter 8 (MCT8), which also interacts with GPCRs.

Purpose of the Study:

• To investigate a potential interaction between MC4R and MCT8 in hypothalamic neurons.
• To elucidate the functional consequences of this MC4R-MCT8 interplay on receptor signaling.

Main Methods:

• Single-cell RNA-sequencing data analysis to confirm co-expression of MC4R and MCT8 in hypothalamic neurons.
• Development of a novel fluorescent staining protocol to demonstrate co-localization of MC4R and MCT8 in human brain tissue.
• In vitro assays including Bioluminescence Resonance Energy Transfer (BRET), inositol phosphate 1 (IP1) accumulation, and cyclic adenosine monophosphate (cAMP) determination.

Main Results:

• MC4R and MCT8 were found to co-localize in human brain tissue.
• MCT8 was shown to modulate MC4R-mediated phospholipase C activation through a direct interaction.
• This modulation of MC4R signaling by MCT8 did not affect cAMP formation and did not require a functional MCT8 transporter.

Conclusions:

• MCT8 exhibits an extended functional role as a modulator of GPCR signaling, specifically impacting MC4R activity.
• The findings support the investigation of further GPCR interactions with proteins possessing underrepresented physiological functions.
• This study highlights a novel mechanism in energy homeostasis regulation involving MC4R and MCT8.