Variations of Corticotropin-Releasing Factor Receptor 1α Contribute to the Blunted HPA Axis Responses to Hypoxia in Plateau Mammals

Corticotropin-releasing factor (CRF) and its receptor (CRFR1) are critical components of the hypothalamic-pituitary-adrenocortical (HPA) axis. Ochotona curzoniae (O. curzoniae), Myospalax baileyi (M. baileyi), and Microtus oeconomus (M. oeconomus) have diversely evolved adaptive strategies to the extreme environment at high altitude. Here, we found blunted HPA axis responsiveness in native Tibetan mammals. CRF was 100% conserved, three amino-acid variations were in M. oeconomus-urocortin (UCN), and unique amino-acid variations in ligand-receptor binding domains of O. curzoniae-, M. baileyi-, and M. oeconomus-CRFR1αs. The native mammals’ binding affinity and cAMP production varied depending on different doses of ligand-CRF/UCN treatment. Variations in M. oeconomus-UCN and O. curzoniae-, M. baileyi-, M. oeconomus-CRFR1α were responsible for weaker CRF-CRFR1α binding and higher EC₅₀. They had the same HPA response pattern as that of CRF-CRFR1α binding affinity, cAMP production, and cell permeability. AlphaFold3.0 predicted altered structural interactions for both CRF-CRFR1α and UCN-CRFR1α complexes corroborate our findings. This study reveals that the variations of UCN/CRFR1α contribute to the different responsiveness of the HPA axis to extreme environments.