GPCRs of Diverse Physiologic and Pathologic Effects with Fingerprints in COVID-19

G-protein-coupled receptors (GPCR) belong to a large family of molecules eliciting different responses to a variety of signaling molecules. These receptors participate in various physiologic pathways such as metabolism, growth, immune responses, inflammation, vision, taste, olfaction, neurotransmission and even and pathologic responses including chronic inflammatory and vascular diseases. Receptors contributing to the biological responses of renin-angiotensin system (RAS) are members of GPCR family. COVID-19-induced inflammatory cascade has been attributed to acute ACE2 downregulation and imbalance of proinflammatory ACE/AngII/AT1R and anti-inflammatory ACE2/angiotensin (1-7)/Mas axes in favor of the former. Some of the receptors contributing to activities of proteins in RAS including AT1R, AT2R and Mas receptors are members of GPCR family. It is notable that these receptors induce their effects both through G protein and β-arrestin pathway; the former exerts temporary and the latter more sustained effects. In addition to the imbalance of GPCR responses contributing to RAS activities, it has been suggested that SARS-CoV2 pathogenesis might be attributed to the activation of GPCRs or modulating G-proteins involved in adenosine-CFTR regulation system and epithelial Na channel function.This article includes a minireview about the physiological functions of GPCRs and their contribution to COVID-19.

In vitro profiling of orphan G protein coupled receptor (GPCR) constitutive activity

Background and PurposeMembers of the G protein coupled receptor (GPCR) family are targeted by a significant fraction of the available FDA-approved drugs. However, the physiological role and pharmacological properties of many GPCRs remain unknown, representing untapped potential in drug design. Of particular interest are ~100 less-studied GPCRs known as orphans because their endogenous ligands are unknown. Intriguingly, disease-causing mutations identified in patients, together with animal studies, have demonstrated that many orphan receptors play crucial physiological roles, and thus, represent attractive drug targets.Experimental ApproachThe majority of deorphanized GPCRs demonstrate coupling to Gi/o, however a limited number of techniques allow the detection of intrinsically small constitutive activity associated with Gi/o protein activation which represents a significant barrier in our ability to study orphan GPCR signaling. Using luciferase reporter assays, we effectively detected constitutive Gs, Gq, and G12/13 protein signaling by unliganded receptors, and introducing various G protein chimeras, we provide a novel, highly-sensitive tool capable of identifying Gi/o coupling in unliganded orphan GPCRs.Key ResultsUsing this approach, we measured the constitutive activity of the entire class C GPCR family that includes 8 orphan receptors, and a subset of 20 prototypical class A GPCR members, including 11 orphans. Excitingly, this approach illuminated the G protein coupling profile of 8 orphan GPCRs (GPR22, GPR137b, GPR88, GPR156, GPR158, GPR179, GPRC5D, and GPRC6A) previously linked to pathophysiological processes.Conclusion and ImplicationsWe provide a new platform that could be utilized in ongoing studies in orphan receptor signaling and deorphanization efforts.What is already knownA large group of understudied orphan GPCRs controls a variety of physiological process.What this study addsA new strategy to identify G protein signaling associated with orphan GPCRs.Identification of Gi/o coupling for 8 orphan GPCRs.What is the clinical significanceMany orphan GPCRs are associated with pathological conditions and represent promising druggable targets.

The Evolutionary History of the Orexin/Allatotropin GPCR Family: From Placozoa and Cnidaria to Vertebrata

ABSTRACTCell-cell communication is a basic principle in all organisms, necessary to facilitate the coordination and integration between cell populations. These systems act by mean of chemical messengers. Peptides constitute a highly diversified group of intercellular messengers widely distributed in nature, and regulate a great number of physiological processes in Metazoa. Being crucial for life, it would seem that they have appeared in the ancestral group from which Metazoa evolved, and were highly conserved along the evolutionary process. Peptides act mainly through G-protein coupled receptors (GPCRs), a great family of transmembrane molecules. GPCRs are also widely distributed in nature being present not only in metazoan, but also in Choanoflagellata (unicellular eukariotes related with metazoans), and even in Fungi. Among GPCRs, the Allatotropin/Orexin (AT/Ox) family is particularly characterized by the presence of the DRWmotif in the second intracellular loop (IC Loop 2), and seems to be present in Cnidaria, Placozoa and in Bilateria, suggesting that it also was present in the common ancestor of Metazoa. Looking for the evolutionary history of this GPCR family we searched in the GenBank for sequences corresponding to this family of receptors (i.e. seven transmembrane domain and the E/DRW motif at the second IC Loop 2). Our results show that AT/Ox receptors were highly conserved along evolutionary history of Metazoa, and that they might be defined by the presence of the E/DRWYAI motif at the level of IC Loop 2. Molecular phylogenetic analyses performed by Maximum Likelihood method suggest that AT/Ox family of receptors reflects evolutionary relationships that agree with current understanding of phylogenetic relationships in Actinopterygii and Sauropsida, including also the largely discussed position of Testudines.

RESEPTOR MELANOKORTIN 1 (MC1R) ASAL USUL DAN STRUKTUR PROTEIN

Melanocytes in basal layers of skin and hair follicles produce melanin biopolymers which determine phenotypes of skin and hair colors of an individual. Melanogenesis induction is influenced by many factors: one of them is activation of receptors in melanocytes’ trans-membrane fragments by effector hormones. Melanocortin-1 receptors belong to the subclasses of the G-protein-coupled-receptor (GPCR) family that is located in melanocytes’ transmem-brane fragments. Variations of their protein structures affect the end result of skin color. Intro-duction, nomenclature, grouping these receptors in the GPCR family, and their protein struc-tures, give some important information about how the receptors actually work in our body, especially in the skin and hair. Key words: GPCR, MC1R, protein’s structure. Abstrak: Sel-sel melanosit pada lapisan basal kulit dan folikel rambut memproduksi biopoli-mer melanin yang akan menentukan fenotip warna kulit dan rambut seseorang. Induksi melanogenesis yang terjadi dipengaruhi oleh banyak faktor, salah satu diantaranya adalah melalui aktivasi reseptor pada transmembran melanosit oleh beberapa hormon efektor. Reseptor melanokortin 1 merupakan sub-sub kelas kelompok reseptor protein G yang terletak pada transmembran melanosit dimana variasi struktur protein penyusunnya akan mempengaruhi hasil akhir warna kulit. Pengenalan awal, tata nama, penggolongannya dalam bagian keluarga besar protein G serta struktur protein setidaknya memberi sedikit pemahaman bagaimana cara kerja reseptor ini selanjutnya. Kata kunci: MC1R, GPCR, struktur protein.