GPCRs of diverse physiologic and pathologic effects with their fingerprints in COVID-19

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.

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