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Single hormone or synthetic agonist induces G_s/G_i coupling selectivity of EP receptors via distinct binding modes and propagating paths.

ABSTRACT: To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, Sci STKE 2001, re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, Nature 402, 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, Nature 390, 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that G_s-biased signaling, but not G_i activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-G_i, EP4-G_s, and EP4-G_i in complex with endogenous prostaglandin E₂ (PGE₂)or two synthetic agonists and comparing with PGE₂-EP2-G_s structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the G_s/G_i transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE₂ ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their G_s/G_i coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for G_s/G_i coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.

SUBMITTER: Huang SM

PROVIDER: S-EPMC10372679 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Single hormone or synthetic agonist induces Gs/Gi coupling selectivity of EP receptors via distinct binding modes and propagating paths.

Huang Shen-Ming SM Xiong Meng-Yao MY Liu Lei L Mu Jianqiang J Wang Ming-Wei MW Jia Ying-Li YL Cai Kui K Tie Lu L Zhang Chao C Cao Sheng S Wen Xin X Wang Jia-Le JL Guo Sheng-Chao SC Li Yu Y Qu Chang-Xiu CX He Qing-Tao QT Cai Bo-Yang BY Xue Chenyang C Gan Shiyi S Xie Yihe Y Cong Xin X Yang Zhao Z Kong Wei W Li Shuo S Li Zijian Z Xiao Peng P Yang Fan F Yu Xiao X Guan You-Fei YF Zhang Xiaoyan X Liu Zhongmin Z Yang Bao-Xue BX Du Yang Y Sun Jin-Peng JP

Proceedings of the National Academy of Sciences of the United States of America 20230721 30

To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, Sci STKE 2001, re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, Nature 402, 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, Nature 390, 88-91 (1997)]. Not only these questi ...[more]

PMID: 37478163

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Project description:AimsTo test the hypothesis that the activation of the growth hormone-releasing hormone (GHRH) receptor signalling pathway within the myocardium both prevents and reverses diastolic dysfunction and pathophysiologic features consistent with heart failure with preserved ejection fraction (HFpEF). Impaired myocardial relaxation, fibrosis, and ventricular stiffness, among other multi-organ morbidities, characterize the phenotype underlying the HFpEF syndrome. Despite the rapidly increasing prevalence of HFpEF, few effective therapies have emerged. Synthetic agonists of the GHRH receptors reduce myocardial fibrosis, cardiomyocyte hypertrophy, and improve performance in animal models of ischaemic cardiomyopathy, independently of the growth hormone axis.Methods and resultsCD1 mice received 4- or 8-week continuous infusion of angiotensin-II (Ang-II) to generate a phenotype with several features consistent with HFpEF. Mice were administered either vehicle or a potent synthetic agonist of GHRH, MR-356 for 4-weeks beginning concurrently or 4-weeks following the initiation of Ang-II infusion. Ang-II-treated animals exhibited diastolic dysfunction, ventricular hypertrophy, interstitial fibrosis, and normal ejection fraction. Cardiomyocytes isolated from these animals exhibited incomplete relaxation, depressed contractile responses, altered myofibrillar protein phosphorylation, and disturbed calcium handling mechanisms (ex vivo). MR-356 both prevented and reversed the development of the pathological phenotype in vivo and ex vivo. Activation of the GHRH receptors increased cAMP and cGMP in cardiomyocytes isolated from control animals but only cAMP in cardiac fibroblasts, suggesting that GHRH-A exert differential effects on cardiomyocytes and fibroblasts.ConclusionThese findings indicate that the GHRH receptor signalling pathway(s) represents a new molecular target to counteract dysfunctional cardiomyocyte relaxation by targeting myofilament phosphorylation and fibrosis. Accordingly, activation of GHRH receptors with potent, synthetic GHRH agonists may provide a novel therapeutic approach to management of the myocardial alterations associated with the HFpEF syndrome.

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Single hormone or synthetic agonist induces G_s/G_i coupling selectivity of EP receptors via distinct binding modes and propagating paths.

Publications

Single hormone or synthetic agonist induces G<sub>s</sub>/G<sub>i</sub> coupling selectivity of EP receptors via distinct binding modes and propagating paths.

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