Recent progress in relaxin-3-related research.

Area of Science:

• Neuroendocrinology
• G-protein coupled receptor research
• Peptide hormone signaling

Background:

• Relaxin-3 (R3) is a brainstem peptide hormone belonging to the insulin (INSL) superfamily.
• R3 has been identified as a ligand for LGR7 and two orphan G-protein coupled receptors (GPCRs): GPCR135 and GPCR142.
• GPCR135 shows predominant brain expression, consistent with R3 localization, suggesting a functional interaction.

Purpose of the Study:

• To elucidate the specific receptor interactions of Relaxin-3 (R3) and its closest family member, INSL5.
• To characterize the roles of GPCR135 and GPCR142 in R3-mediated signaling.
• To develop selective ligands for these GPCRs.

Main Methods:

• Ligand-receptor binding assays to determine affinities and selectivities.
• Analysis of gene and protein expression patterns for R3, INSL5, GPCR135, and GPCR142 across species.
• Construction and pharmacological evaluation of a chimeric peptide (R3/I5).
• Autoradiography to map GPCR135 binding sites in the rat brain.

Main Results:

• R3 is confirmed as the endogenous ligand for brain-expressed GPCR135 due to high affinity and conserved expression.
• INSL5 acts as an agonist for GPCR142, which is primarily expressed in peripheral tissues and is less conserved in rodents.
• A chimeric peptide (R3/I5) demonstrated high selectivity (>1000-fold) for GPCR135 and GPCR142 over LGR7.
• GPCR135 binding sites are concentrated in rat brain regions involved in sensory signal processing.

Conclusions:

• R3 is the primary endogenous ligand for GPCR135 in the brain, playing a role in sensory processing.
• INSL5 likely serves as the endogenous ligand for peripheral GPCR142.
• The chimeric peptide R3/I5 represents a valuable tool for studying GPCR135 and GPCR142 pharmacology.