Recently, Prof. Yu Xiao and Prof. Sun Jinpeng from the School of Basic Medical Sciences of Shandong University, Prof. Lin Haocheng from Peking University Third Hospital and Prof. Xu Wenming from West China Second University Hospital collaborated in publishing a research paper entitled “Activation of PTH1R alleviates epididymitis and orchitis through Gq and β-arrestin-1 pathways " in Proceedings of the National Academy of Sciences of the United States of America (PNAS). PhD candidate Wang Mingwei and assistant professor Yang Zhao from the School of Basic Medical Sciences of Shandong University are co-first authors of this paper. Professors Sun Jinpeng, Yu Xiao, Lin Haocheng and Xu Wenming are co-corresponding authors. Shandong University is the first institute of this paper.

Currently, male infertility has become a public health issue. The inflammations in the epididymis and testis are estimated to account for 6 to 15% of male infertility and have attracted increasing attention. Conventional therapies for epididymitis and orchitis using antibiotics have limitations in terms of side effects and ineffectiveness for nonbacterial inflammations, thus highlighting an urgent need for novel therapeutic strategies. The researchers demonstrated that type 1 parathyroid hormone receptor (PTH1R) and its endogenous agonists, parathyroid hormone (PTH) and PTH-related protein (PTHrP), were expressed in the Leydig cells of testis as well as epididymal epithelial cells. Screening the secretin family G protein-coupled receptor (GPCR) identified that PTH1R in the epididymis and testis was down-regulated in mumps virus (MuV)- or lipopolysaccharide (LPS)-induced inflammation. Remarkably, activation of PTH1R by abaloparatide (ABL), an FDA–approved treatment for postmenopausal osteoporosis, alleviated MuV- or LPS-induced inflammatory responses in both testis and epididymis and significantly improved sperm functions. Using a combination of pharmacological approaches and gene knockout mice, the researchers demonstrated that the anti-inflammatory effects of ABL were primarily regulated through the Gq and β-arrestin-1 pathway downstream of PTH1R. The results identified an important immunoregulatory role for PTH1R signaling in the epididymis and testis, suggesting that selectively targeting the Gq or β-arrestin-1 pathway of PTH1R might have a therapeutic effect for the treatment of epididymitis and orchitis.

Professor Sun Jinpeng and professor Yu Xiao’s research groups focus on the molecular mechanism and physiological significance of GPCR biased signaling. In previous studies, they have elucidated the detailed mechanisms underlying the regulation of learning and memory by β-adrenergic receptor through β-arrestin-1 pathway (Biol Psychiatry, 2017), the fast coupling and activation of TPRC3 channel by angiotensin II type I receptor through β-arrestin-1 (Nat Commun, 2017), and the accurate regulation of fluid reabsorption and pH homeostasis in the efferent ductules by the ADGRG2/Gq/β-arrestin-1/CFTR signaling complex (Elife, 2018). Professor Sun Jinpeng and professor Yu Xiao cooperate closely in the PTH1R research field with Professor Zhang Yan from Zhejiang University, who previously resolved the Cryo-EM structure of PTH1R-Gs complex and laid a solid foundation for the present work. This work was supported by professor Jiang Hui from Peking University Third Hospital and professor Li Jianyuan from the Key Laboratory of Male Reproductive Health, National Health and Family Planning Commission. The above research was supported by the National Key Basic Research Program of China and the National Natural Science Foundation of China.

Link to this paper:

https://www.pnas.org/content/118/45/e2107363118.long