The cloned equine thyrotropin receptor is hypersensitive to human chorionic gonadotropin; identification of three residues in the extracellular domain involved in ligand specificity.

The research article discusses the cloning and functional characterization of the equine thyrotropin receptor (TSHR) and its high sensitivity to human chorionic gonadotropin (CG). It reveals that the equine TSHR’s specific adaptation is due to three distinct residues in its ectodomain, implying that glycoprotein hormone receptors may have evolved differently among different species in response to new hormones.

Understanding the Research

• The research pertains to a certain class of G protein-coupled receptors, which include receptors for thyrotropin (TSH), luteinizing hormone/chorionic gonadotropin (LH/CG), and follicle-stimulating hormone (FSH). These receptors interact specifically with their respective hormones, a specificity primarily determined by certain residues present in the leucine-rich repeats of the receptor’s N-terminal ectodomain.
• The secretion of CG – a hormone involved in pregnancy – is exclusive to primates and equine species. Receptors for these glycoprotein hormones are hypothesized to have evolved differently in humans and equines in response to this unique hormone, implying differences in the residues contributing to hormone specificity.
• The researchers used the phylogenetic approach, which analyses hereditary relationships and species evolution, to identify the determinants of receptor specificity.

About the Equine TSH Receptor

• The research team cloned and functionally characterized the equine TSH receptor (TSHR), finding an 89% genetic homology or similarity with the human TSHR.
• Interestingly, the equine TSHR was unresponsive to equine CG, but demonstrated hypersensitivity to human CG – greater sensitivity compared to the human TSHR’s response to human CG.

A Closer Look at the Determinants

• Differences in sensitivity towards human CG were attributed to three distinct residues at positions 60, 229, and 235 of the receptor’s ectodomain. The team reached this conclusion through targeted mutagenesis and in vitro functional characterization – techniques used to modify genetic material and test the modified genes’ functions, respectively.
• These findings reinforce the notion that glycoprotein hormone receptors may have undergone unique evolutionary adaptations in response to new hormones, evidencing species-specific evolutionary traits.