Selective Colocalization of GHSR and GLP-1R in a Subset of Hypothalamic Neurons and Their Functional Interaction

Area of Science:

• Neuroscience
• Endocrinology
• Molecular Biology

Background:

• The GH secretagogue receptor (GHSR) and glucagon-like peptide-1 receptor (GLP-1R) are G protein-coupled receptors crucial for energy balance.
• These receptors are found in overlapping brain regions, raising questions about neuronal colocalization and molecular crosstalk.

Purpose of the Study:

• To investigate the colocalization of GHSR and GLP-1R in specific neurons within the mouse brain.
• To explore potential molecular crosstalk between GHSR and GLP-1R signaling pathways.

Main Methods:

• Detailed mapping of GHSR and GLP-1R expressing cells using reporter mice and fluorescent ligands.
• Analysis of RNA-sequencing datasets from mouse and human brains.
• Functional studies using patch-clamp recordings in a heterologous expression system.

Main Results:

• GHSR and GLP-1R expressing cells are largely segregated in the mouse brain, with minimal overlap (<20%) primarily in the hypothalamic arcuate nucleus.
• RNA-sequencing data confirmed high segregation of double-positive neurons (<10% of total).
• Functional studies demonstrated that GLP-1R activation inhibits presynaptic calcium channels, and this effect is attenuated by the presence of GHSR, indicating molecular crosstalk.

Conclusions:

• GHSR and GLP-1R are predominantly expressed in distinct neuronal populations within the brain.
• Despite segregation, GHSR and GLP-1R can engage in molecular crosstalk, influencing presynaptic calcium channel activity.