Variations of Corticotropin-Releasing Factor Receptor 1α Contribute to the Blunted HPA Axis Responses to Hypoxia in Plateau Mammals
Jiafang Yang1,2,3 · Fangyuan Xia1,2 · Hao Jin2 · Chatoo Mahanand1,2 · Huiqi Lin4 · Yibin Cao5 · Jianghui Bian6 · Dengbang Wei7 · Eviatar Nevo8 · Jizeng Du1,2 · Shumin Duan2,9 · Fang Guo2,10 · Yang Zhao4 · Xuequn Chen1,2
1 Department of Neurology of the Second Affiliated Hospital, School of Brain Sciences and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310016, China
2 NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
3 Zhaoqing Medical College, Zhaoqing 526000, China
4 Department of Physiology and Department of Hepatobiliary and Pancreatic Surgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
5 College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321000, China
6 Northwest Plateau Institute of Biology, Chinese Academy of Sciences, Xining 810001, China
7 State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining 810003, China
8 Institute of Evolution and International Graduate Center of Evolution, University of Haifa, Mount Carmel, 3498838 Haifa, Israel
9 MOE Frontier Science Center for Brain Science and Brain‑Machine Integration, State Key Laboratory of Brain‑Machine Intelligence, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310016, China
10 Department of Neurobiology, Department of Neurology of Sir Run Run Shaw Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China
Abstract
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.
Keywords
CRF; CRFR1α; HPA; cAMP; Extreme environment; Stress
