Please login first
GPCRs of diverse physiologic and pathologic effects with their fingerprints in COVID-19
* 1, 2 , 3, 4 , 5, 6
1  former Assistant Prof., Shahid Beheshti University of Medical Sciences;
2  former ICU Chief, Bazarganan Hospital, Tehran, Iran
3  Bioinformatics Research Center, Cheragh Medical Institute and Hospital, Kabul, Afghanistan
4  Department of Computer and data Sciences, Faculty of Mathematical Sciences, Shahid Beheshti University, Tehran, Iran
5  Assistant Clinical Prof., Shiley Eye Institutem UCSD, California, USA
6  Alliance Retinal Consultant, La Mesa, California, USA


G-protein-coupled receptors (GPCR), a seven-transmembrane α-helical domain protein, contribute to many physiologic functions including vision, olfaction and taste and also to several pathologic processes including hypersensitivity to angiotensin II, inflammatory and vascular diseases [1, 2]. GPCRs in binding with agonistic ligands adopt a proton-transport dependent conformational change and activate cytoplasmic heterotrimeric G proteins (Gα/Gβγ subunits) through dissociation of Gα from Gβγ complex and exchange of GTP for GDP in Gα subunit [3, 4]. This activates a second messenger including cAMP, Ca2+, diacylglycerol which induces some intracellular pathways such as MAPK, PI3K-Akt and Ras and Rho GTPases [5]. Moreover, GPCR activation promotes receptor phosphorylation by GPCR-kinase with subsequent binding of β-arrestin which induces G-protein independent signaling cascades [6, 7].

COVID-19-induced inflammatory cascade has been attributed to ACE2 downregulation and imbalance of proinflammatory ACE/AngII/AT1R and anti-inflammatory ACE2/Angiotensin(1-7)/Mas axes in favor of the former [8]. AT1R, AT2R and Mas receptors belong to GPCR family [9, 10]. While sustained AngII activation of AT1R induces inflammatory responses through G-proteins, angiotensin(1-7) promotes anti-inflammatory effects both via Mas/GPCR receptors and AT1R/GPCR mediated β-arrestin pathway [11]. SARS-CoV2 has been suggested to induce lung edema via activation of GPCRs or modulating G-proteins involved in adenosine-CFTR regulation system and epithelial Na channel function [12]. Complement 5a receptor1 (C5aR1), a member of GPCR family, has recently been proposed to be involved in COVID-19 pathogenesis [13]. GPCR4, which regulates vascular permeability and leukocyte recruitment, has been hypothesized to play a part in SARS-CoV2 infection [14].
In this article the role of GPCRs in the body and in COVID-19 are discussed.

1. Quitterer, U. and S. AbdAlla, Discovery of pathologic GPCR aggregation. Frontiers in medicine, 2019. 6: p. 9.
2. Zalewska, M., M. Siara, and W. Sajewicz, G protein-coupled receptors: abnormalities in signal transmission, disease states and pharmacotherapy. Acta Pol Pharm, 2014. 71(2): p. 229-243.
3. Rajagopal, S., K. Rajagopal, and R.J. Lefkowitz, Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nature reviews Drug discovery, 2010. 9(5): p. 373-386.
4. Zhang, X.C., et al., Proton transfer-mediated GPCR activation. Protein & cell, 2015. 6(1): p. 12-17.
5. Walsh, C.T., D. Stupack, and J.H. Brown, G Protein–Coupled Receptors Go Extracellular: RhoA Integrates the Integrins. Molecular interventions, 2008. 8(4): p. 165.
6. Tilley, D.G., G protein–dependent and G protein–independent signaling pathways and their impact on cardiac function. Circulation research, 2011. 109(2): p. 217-230.
7. Peterson, Y.K. and L.M. Luttrell, The diverse roles of arrestin scaffolds in G protein–coupled receptor signaling. Pharmacological reviews, 2017. 69(3): p. 256-297.
8. Nejat, R. and A.S. Sadr, Are losartan and imatinib effective against SARS-CoV2 pathogenesis? A pathophysiologic-based in silico study. In silico pharmacology, 2021. 9(1): p. 1-22.
9. Magnani, F., et al., Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II. ACS chemical biology, 2014. 9(7): p. 1420-1425.
10. Santos, R.A., et al., Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proceedings of the National Academy of Sciences, 2003. 100(14): p. 8258-8263.
11. Manglik, A., et al., β-Arrestin–Biased Angiotensin II Receptor Agonists for COVID-19. Circulation, 2020. 142(4): p. 318-320.
12. Hameid, R.A., et al., SARS-CoV-2 may hijack GPCR signaling pathways to dysregulate lung ion and fluid transport. American Physiological Society Rockville, MD.
13. Carvelli, J., et al., Association of COVID-19 inflammation with activation of the C5a–C5aR1 axis. Nature, 2020: p. 1-5.
14. Yang, L.V., et al., Can GPR4 Be a Potential Therapeutic Target for COVID-19? Frontiers in medicine, 2021. 7: p. 1150.

Keywords: GPCR, AT1R, AT2R, Mas receptor, angiotensin (1-7), ang II, COVID-19, GTPase, GDP, G protein, PI3K-Akt, cAMP, Ca, diacylglycerol