|
|
Pharmacy Information 2026
G蛋白偶联受体在皮肤与免疫系统中的信号偏向性与下游通路网络互作研究进展
|
Abstract:
G蛋白偶联受体(G Protein-Coupled Receptor, GPCR)是人体内最大的受体家族，参与了广泛的生理过程，并且是许多药物的重要靶点。近年来，研究发现GPCR的配体(ligands)可以通过稳定受体的特定构象，从而选择性地激活下游的某些信号通路，这种现象被称为“信号偏向性”(biased signaling)。这一发现为设计更精准、副作用更小的药物提供了新的思路。本文综述了GPCR激活的经典机制、信号偏向性的分子基础，以及GPCR下游信号通路的核心组成部分，包括cAMP-PKA、PLC-PKC、PI3K-Akt及MAPK级联通路等，聚焦皮肤及免疫系统相关GPCR，并探讨了它们与关键转录因子的调控网络。同时，系统介绍偏向性定量分析方法及不同细胞背景对偏向性评估的影响。文章重点阐述了GPCR偏向性信号产生的机制，包括配体本身带来的偏向、受体自身构象的偏向以及细胞内系统的差异带来的偏向。同时，介绍了近年来结构生物学研究在揭示偏向信号分子机制方面取得的新进展。此外，本文还讨论了GPCR信号通路之间的交叉互作，例如GPCR介导的mTORC2-Akt通路和TGF-β受体通路的整合，以及这些交叉信号在疾病研究和药物开发中的重要意义。最后，对GPCR信号偏向性领域未来的发展方向和面临的挑战进行了展望。
G Protein-Coupled Receptors (GPCRs) represent the largest receptor family in the human body, participate in a wide range of physiological processes, and serve as important targets for many therapeutic drugs. In recent years, studies have shown that GPCR ligands can selectively activate specific downstream signaling pathways by stabilizing distinct receptor conformations, a phenomenon known as biased signaling. This discovery has provided new strategies for the development of more precise drugs with reduced adverse effects. This review summarizes the classical mechanisms of GPCR activation, the molecular basis of biased signaling, and the core components of GPCR downstream signaling pathways, including the cAMP-PKA, PLC-PKC, PI3K-Akt, and MAPK cascades. Particular attention is given to GPCRs related to the skin and immune systems, and their regulatory networks with key transcription factors are discussed. In addition, quantitative methods for assessing signaling bias are systematically introduced, along with the influence of different cellular contexts on bias evaluation. The mechanisms underlying GPCR biased signaling are highlighted, including ligand-induced bias, receptor conformational bias, and system-dependent bias arising from intracellular signaling differences. Recent advances in structural biology that have contributed to elucidating the molecular mechanisms of biased signaling are also reviewed. Furthermore, cross-talk among GPCR signaling pathways is discussed, such as the integration of GPCR-mediated mTORC2-Akt signaling with TGF-β receptor pathways, as well as the significance of these interactions in disease research and drug development. Finally, future directions and challenges in the field of GPCR biased signaling are discussed.
| [1] | Mahoney, J.P. and Sunahara, R.K. (2016) Mechanistic Insights into GPCR-G Protein Interactions. Current Opinion in Structural Biology, 41, 247-254. https://doi.org/10.1016/j.sbi.2016.11.005 |
| [2] | Inoue, A., Raimondi, F., Kadji, F.M.N., Singh, G., Kishi, T., Uwamizu, A., et al. (2019) Illuminating G-Protein-Coupling Selectivity of GPCRs. Cell, 177, 1933-1947.e25. https://doi.org/10.1016/j.cell.2019.04.044 |
| [3] | Farrens, D.L., Altenbach, C., Yang, K., Hubbell, W.L. and Khorana, H.G. (1996) Requirement of Rigid-Body Motion of Transmembrane Helices for Light Activation of Rhodopsin. Science, 274, 768-770. https://doi.org/10.1126/science.274.5288.768 |
| [4] | Rasmussen, S.G.F., DeVree, B.T., Zou, Y., Kruse, A.C., Chung, K.Y., Kobilka, T.S., et al. (2011) Crystal Structure of the Β2 Adrenergic Receptor-Gs Protein Complex. Nature, 477, 549-555. https://doi.org/10.1038/nature10361 |
| [5] | Szczepek, M., Beyrière, F., Hofmann, K.P., Elgeti, M., Kazmin, R., Rose, A., et al. (2014) Crystal Structure of a Common GPCR-Binding Interface for G Protein and Arrestin. Nature Communications, 5, Article No. 4801. https://doi.org/10.1038/ncomms5801 |
| [6] | Carpenter, B., Nehmé, R., Warne, T., Leslie, A.G.W. and Tate, C.G. (2016) Structure of the Adenosine A2A Receptor Bound to an Engineered G Protein. Nature, 536, 104-107. https://doi.org/10.1038/nature18966 |
| [7] | Liang, Y., Khoshouei, M., Radjainia, M., Zhang, Y., Glukhova, A., Tarrasch, J., et al. (2017) Phase-plate Cryo-Em Structure of a Class B GPCR-g-Protein Complex. Nature, 546, 118-123. https://doi.org/10.1038/nature22327 |
| [8] | Zhang, Y., Sun, B., Feng, D., Hu, H., Chu, M., Qu, Q., et al. (2017) Cryo-EM Structure of the Activated GLP-1 Receptor in Complex with a G Protein. Nature, 546, 248-253. https://doi.org/10.1038/nature22394 |
| [9] | Che, T., Majumdar, S., Zaidi, S.A., Ondachi, P., McCorvy, J.D., Wang, S., et al. (2018) Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor. Cell, 172, 55-67.e15. https://doi.org/10.1016/j.cell.2017.12.011 |
| [10] | Scheerer, P., Park, J.H., Hildebrand, P.W., Kim, Y.J., Krauß, N., Choe, H., et al. (2008) Crystal Structure of Opsin in Its G-Protein-Interacting Conformation. Nature, 455, 497-502. https://doi.org/10.1038/nature07330 |
| [11] | Vedel, L., Bräuner-Osborne, H. and Mathiesen, J.M. (2015) A cAMP Biosensor-Based High-Throughput Screening Assay for Identification of GS-Coupled GPCR Ligands and Phosphodiesterase Inhibitors. SLAS Discovery, 20, 849-857. https://doi.org/10.1177/1087057115580019 |
| [12] | Katoh, (2009) Integrative Genomic Analyses on GLI1: Positive Regulation of GLI1 by Hedgehog-GLI, TGFβ-SMADs, and RTK-PI3K-AKT Signals, and Negative Regulation of GLI1 by Notch-CSL-HES/Hey, and GPCR-GS-PKA Signals. International Journal of Oncology, 35, 187-192. https://doi.org/10.3892/ijo_00000328 |
| [13] | Nakajima, K., Cui, Z., Li, C., Meister, J., Cui, Y., Fu, O., et al. (2016) GS-Coupled GPCR Signalling in AGRP Neurons Triggers Sustained Increase in Food Intake. Nature Communications, 7, Article 10268. https://doi.org/10.1038/ncomms10268 |
| [14] | Kalogriopoulos, N.A., Rees, S.D., Ngo, T., Kopcho, N.J., Ilatovskiy, A.V., Sun, N., et al. (2019) Structural Basis for GPCR-Independent Activation of Heterotrimeric Gi Proteins. Proceedings of the National Academy of Sciences, 116, 16394-16403. https://doi.org/10.1073/pnas.1906658116 |
| [15] | 楼晓波, 金洪传. G蛋白偶联受体转激活受体酪氨酸激酶的研究进展[J]. 浙江大学学报(医学版), 2008, 37(1): 92-96. |
| [16] | Vo, A.P., Kim, S., Yang, M.Y., Ondrus, A.E. and Goddard, W.A. (2023) Fully Activated Structure of the Sterol-Bound Smoothened GPCR-Gi Protein Complex. Proceedings of the National Academy of Sciences, 120, e2309240120. https://doi.org/10.1073/pnas.2300919120 |
| [17] | Cvetkovic, C., Patel, R., Shetty, A., Hogan, M.K., Anderson, M., Basu, N., et al. (2022) Assessing Gq-GPCR-Induced Human Astrocyte Reactivity. Journal of Cell Biology, 221, e202107135. https://doi.org/10.1083/jcb.202107135 |
| [18] | Vail, G. and Roepke, T.A. (2019) Membrane-initiated Estrogen Signaling via Gq-Coupled GPCR in the Central Nervous System. Steroids, 142, 77-83. https://doi.org/10.1016/j.steroids.2018.01.010 |
| [19] | Nagai, J., Bellafard, A., Qu, Z., Yu, X., Ollivier, M., Gangwani, M.R., et al. (2021) Specific and Behaviorally Consequential Astrocyte Gq GPCR Signaling Attenuation in Vivo with Iβark. Neuron, 109, 2256-2274.e9. https://doi.org/10.1016/j.neuron.2021.05.023 |
| [20] | Thomsen, W., Frazer, J. and Unett, D. (2005) Functional Assays for Screening GPCR Targets. Current Opinion in Biotechnology, 16, 655-665. https://doi.org/10.1016/j.copbio.2005.10.008 |
| [21] | Roth, B.L. and Chuang, D. (1987) Multiple Mechanisms of Serotonergic Signal Transduction. Life Sciences, 41, 1051-1064. https://doi.org/10.1016/0024-3205(87)90621-7 |
| [22] | Jarpe, M.B., Knall, C., Mitchell, F.M., Buhl, A.M., Duzic, E. and Johnson, G.L. (1998) [D-Arg1,D-Phe5,D-Trp7,9,Leu11]Substance P Acts as a Biased Agonist. Journal of Biological Chemistry, 273, 3097-3104. https://doi.org/10.1074/jbc.273.5.3097 |
| [23] | Reiter, E., Ahn, S., Shukla, A.K. and Lefkowitz, R.J. (2012) Molecular Mechanism of Beta-Arrestin-Biased Agonism. Annual Review of Pharmacology and Toxicology, 52, 179-197. https://doi.org/10.1146/annurev.pharmtox.010909.105800 |
| [24] | Violin, J.D. and Lefkowitz, R.J. (2007) β-Arrestin-Biased Ligands at Seven-Transmembrane Receptors. Trends in Pharmacological Sciences, 28, 416-422. https://doi.org/10.1016/j.tips.2007.06.006 |
| [25] | Li, A., Liu, S., Huang, R., Ahn, S. and Lefkowitz, R.J. (2023) Loss of Biased Signaling at a G Protein-Coupled Receptor in Overexpressed Systems. PLOS ONE, 18, e0283477. https://doi.org/10.1371/journal.pone.0283477 |
| [26] | Liu, J., Tang, H., Xu, C., Zhou, S., Zhu, X., Li, Y., et al. (2022) Biased Signaling Due to Oligomerization of the Platelet-Activating Factor Receptor. Nature Communications, 13, Article No. 6365. https://doi.org/10.1038/s41467-022-34056-4 |
| [27] | Kenakin, T. (2003) Ligand-Selective Receptor Conformations Revisited. Trends in Pharmacological Sciences, 24, 346-354. https://doi.org/10.1016/s0165-6147(03)00167-6 |
| [28] | Perez, D.M. and Karnik, S.S. (2005) Multiple Signaling States of G-Protein-Coupled Receptors. Pharmacological Reviews, 57, 147-161. https://doi.org/10.1124/pr.57.2.2 |
| [29] | Mukhopadhyay, S. and Howlett, A.C. (2005) Chemically Distinct Ligands Promote Differential CB1 Cannabinoid Receptor-Gi Protein Interactions. Molecular Pharmacology, 67, 2016-2024. https://doi.org/10.1124/mol.104.003558 |
| [30] | Avet, C., Mancini, A., Breton, B., Le Gouill, C., Hauser, A.S., Normand, C., et al. (2022) Effector Membrane Translocation Biosensors Reveal Coupling Profiles of 100 GPCRs. eLife, 11, e74102. https://doi.org/10.7554/elife.74101 |
| [31] | Kim, J., et al. (2020) Structure of the Angiotensin Receptor Revealed the Molecular Mechanism of β-Arrestin-Biased Signaling. Cell, 182, 1-13. |
| [32] | Viscusi, E.R., Skobieranda, F., Soergel, D.G., Cook, E., Burt, D.A. and Singla, N. (2019) Apollo-1: A Randomized Placebo and Active-Controlled Phase III Study Investigating Oliceridine (TRV130), a G Protein-Biased Ligand at the µ-Opioid Receptor, for Management of Moderate-To-Severe Acute Pain Following Bunionectomy. Journal of Pain Research, 12, 927-943. https://doi.org/10.2147/jpr.s171013 |
| [33] | Mohamed, R., Shajimoon, A., Afroz, R., Gabr, M., Thomas, W.G., Little, P.J., et al. (2021) Akt Acts as a Switch for GPCR Transactivation of the TGF‐β Receptor Type 1. The FEBS Journal, 289, 2642-2656. https://doi.org/10.1111/febs.16297 |
| [34] | Senoo, H., Wai, M., Matsubayashi, H.T., Sesaki, H. and Iijima, M. (2020) Hetero-Oligomerization of Rho and Ras Gtpases Connects GPCR Activation to mTORC2-Akt Signaling. Cell Reports, 33, Article 108427. https://doi.org/10.1016/j.celrep.2020.108427 |
| [35] | Chompunud Na Ayudhya, C., Amponnawarat, A. and Ali, H. (2021) Substance P Serves as a Balanced Agonist for MRGPRX2 and a Single Tyrosine Residue Is Required for β-Arrestin Recruitment and Receptor Internalization. International Journal of Molecular Sciences, 22, Article 5318. https://doi.org/10.3390/ijms22105318 |
| [36] | McNeil, B.D., Pundir, P., Meeker, S., Han, L., Undem, B.J., Kulka, M., et al. (2014) Identification of a Mast-Cell-Specific Receptor Crucial for Pseudo-Allergic Drug Reactions. Nature, 519, 237-241. https://doi.org/10.1038/nature14022 |
| [37] | Dainichi, T., Nakano, Y., Doi, H., Nakamizo, S., Nakajima, S., Matsumoto, R., et al. (2022) C10orf99/GPR15L Regulates Proinflammatory Response of Keratinocytes and Barrier Formation of the Skin. Frontiers in Immunology, 13, Article ID: 825032. https://doi.org/10.3389/fimmu.2022.825032 |
| [38] | Gu, Y., Wang, Y., Lan, Y., Feng, J., Zeng, W., Zhang, W., et al. (2022) Expression of Retinal G Protein-Coupled Receptor, a Member of the Opsin Family, in Human Skin Cells and Its Mediation of the Cellular Functions of Keratinocytes. Frontiers in Cell and Developmental Biology, 10, Article ID: 836798. https://doi.org/10.3389/fcell.2022.787730 |
| [39] | Black, J.W. and Leff, P. (1983) Operational Models of Pharmacological Agonism. Proceedings of the Royal Society of London. Series B. Biological Sciences, 220, 141-162. https://doi.org/10.1098/rspb.1983.0093 |
| [40] | Kenakin, T. and Christopoulos, A. (2012) Signalling Bias in New Drug Discovery: Detection, Quantification and Therapeutic Impact. Nature Reviews Drug Discovery, 12, 205-216. https://doi.org/10.1038/nrd3954 |
| [41] | Kenakin, T. (2024) Agonism and Biased Signaling in Pharmacology. Pharmacological Reviews, 76, Article ID e00331. |
| [42] | Kolb, P., Kenakin, T., Alexander, S.P.H., Bermudez, M., Bohn, L.M., Breinholt, C.S., et al. (2022) Community Guidelines for GPCR Ligand Bias: IUPHAR Review 32. British Journal of Pharmacology, 179, 3651-3674. https://doi.org/10.1111/bph.15811 |
| [43] | Staus, D.P., Hu, H., Robertson, M.J., Kleinhenz, A.L.W., Wingler, L.M., Capel, W.D., et al. (2020) Structure of the M2 Muscarinic Receptor-β-Arrestin Complex in a Lipid Nanodisc. Nature, 579, 297-302. https://doi.org/10.1038/s41586-020-1954-0 |
