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G Protein-Coupled Receptors: Signaling and Regulation
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G Protein-Coupled Receptors: Signaling and Regulation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 10483

Special Issue Editor

Prof. Dr. Kyeong-Man Kim

E-Mail Website
Guest Editor
College of Pharmacy, Chonnam National University, Gwang-Ju 61186, Republic of Korea
Interests: GPCR; dopamine receptor; nicotine receptor; signaling; desensitization; endocytosis

Special Issue Information

Dear Colleagues,

G protein-coupled receptors (GPCRs) constitute a family of membrane proteins that transduce exterior stimuli into intracellular signals. Nearly 800 human genes have been predicted to encode GPCRs, and 30–40% of all currently prescribed drugs target GPCRs. Research on GPCR is progressing rapidly in a wide variety of fields. In particular, recent progress in understanding 3D structures and the conceptual advances showing that GPCRs transduce signals through pathways other than G proteins is noteworthy. GPCRs are expected to greatly improve accuracy, speed, and diversity in the development of ligands for related diseases. Most conceptual principles for regulation of GPCR, such as desensitization, have been established as textbook models based on the study of β2 adrenergic receptors. Considering that GPCRs have very diverse structures and signaling systems, they are expected to be regulated through various pathways. In order to derive a principle that can encompass all GPCRs or to organize the information currently scattered in disorder, it is essential to integrate and analyze the results obtained through more diverse viewpoints. This Special Issue aims to develop new therapeutic agents based on basic research and welcomes the submission of original research papers or reviews in the field of signaling and regulation of GPCRs from various perspectives.

Prof. Dr. Kyeong-Man Kim
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • G protein-coupled receptors
  • signal
  • regulation
  • ligands
  • 3D structure
  • drug discovery

Published Papers (5 papers)

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Research

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13 pages, 1936 KiB  
Article
Functional Role of Arrestin-1 Residues Interacting with Unphosphorylated Rhodopsin Elements
by Sergey A. Vishnivetskiy, Liana D. Weinstein, Chen Zheng, Eugenia V. Gurevich and Vsevolod V. Gurevich
Int. J. Mol. Sci. 2023, 24(10), 8903; https://doi.org/10.3390/ijms24108903 - 17 May 2023
Viewed by 916
Abstract
Arrestin-1, or visual arrestin, exhibits an exquisite selectivity for light-activated phosphorylated rhodopsin (P-Rh*) over its other functional forms. That selectivity is believed to be mediated by two well-established structural elements in the arrestin-1 molecule, the activation sensor detecting the active conformation of rhodopsin [...] Read more.
Arrestin-1, or visual arrestin, exhibits an exquisite selectivity for light-activated phosphorylated rhodopsin (P-Rh*) over its other functional forms. That selectivity is believed to be mediated by two well-established structural elements in the arrestin-1 molecule, the activation sensor detecting the active conformation of rhodopsin and the phosphorylation sensor responsive to the rhodopsin phosphorylation, which only active phosphorylated rhodopsin can engage simultaneously. However, in the crystal structure of the arrestin-1–rhodopsin complex there are arrestin-1 residues located close to rhodopsin, which do not belong to either sensor. Here we tested by site-directed mutagenesis the functional role of these residues in wild type arrestin-1 using a direct binding assay to P-Rh* and light-activated unphosphorylated rhodopsin (Rh*). We found that many mutations either enhanced the binding only to Rh* or increased the binding to Rh* much more than to P-Rh*. The data suggest that the native residues in these positions act as binding suppressors, specifically inhibiting the arrestin-1 binding to Rh* and thereby increasing arrestin-1 selectivity for P-Rh*. This calls for the modification of a widely accepted model of the arrestin–receptor interactions. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling and Regulation)
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13 pages, 3770 KiB  
Article
Structural and Functional Implication of Natural Variants of Gαs
by Yejin Jeong and Ka Young Chung
Int. J. Mol. Sci. 2023, 24(4), 4064; https://doi.org/10.3390/ijms24044064 - 17 Feb 2023
Cited by 1 | Viewed by 1877
Abstract
Heterotrimeric guanine nucleotide-binding proteins (G proteins) are among the most important cellular signaling components, especially G protein-coupled receptors (GPCRs). G proteins comprise three subunits, Gα, Gβ, and Gγ. Gα is the key subunit, and its structural state regulates the active status of G [...] Read more.
Heterotrimeric guanine nucleotide-binding proteins (G proteins) are among the most important cellular signaling components, especially G protein-coupled receptors (GPCRs). G proteins comprise three subunits, Gα, Gβ, and Gγ. Gα is the key subunit, and its structural state regulates the active status of G proteins. Interaction of guanosine diphosphate (GDP) or guanosine triphosphate (GTP) with Gα switches G protein into basal or active states, respectively. Genetic alteration in Gα could be responsible for the development of various diseases due to its critical role in cell signaling. Specifically, loss-of-function mutations of Gαs are associated with parathyroid hormone-resistant syndrome such as inactivating parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrP) signaling disorders (iPPSDs), whereas gain-of-function mutations of Gαs are associated with McCune–Albright syndrome and tumor development. In the present study, we analyzed the structural and functional implications of natural variants of the Gαs subtype observed in iPPSDs. Although a few tested natural variants did not alter the structure and function of Gαs, others induced drastic conformational changes in Gαs, resulting in improper folding and aggregation of the proteins. Other natural variants induced only mild conformational changes but altered the GDP/GTP exchange kinetics. Therefore, the results shed light on the relationship between natural variants of Gα and iPPSDs. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling and Regulation)
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16 pages, 3273 KiB  
Article
The Role of Arrestin-1 Middle Loop in Rhodopsin Binding
by Sergey A. Vishnivetskiy, Elizabeth K. Huh, Preethi C. Karnam, Samantha Oviedo, Eugenia V. Gurevich and Vsevolod V. Gurevich
Int. J. Mol. Sci. 2022, 23(22), 13887; https://doi.org/10.3390/ijms232213887 - 11 Nov 2022
Cited by 2 | Viewed by 1723
Abstract
Arrestins preferentially bind active phosphorylated G protein-coupled receptors (GPCRs). The middle loop, highly conserved in all arrestin subtypes, is localized in the central crest on the GPCR-binding side. Upon receptor binding, it directly interacts with bound GPCR and demonstrates the largest movement of [...] Read more.
Arrestins preferentially bind active phosphorylated G protein-coupled receptors (GPCRs). The middle loop, highly conserved in all arrestin subtypes, is localized in the central crest on the GPCR-binding side. Upon receptor binding, it directly interacts with bound GPCR and demonstrates the largest movement of any arrestin element in the structures of the complexes. Comprehensive mutagenesis of the middle loop of rhodopsin-specific arrestin-1 suggests that it primarily serves as a suppressor of binding to non-preferred forms of the receptor. Several mutations in the middle loop increase the binding to unphosphorylated light-activated rhodopsin severalfold, which makes them candidates for improving enhanced phosphorylation-independent arrestins. The data also suggest that enhanced forms of arrestin do not bind GPCRs exactly like the wild-type protein. Thus, the structures of the arrestin-receptor complexes, in all of which different enhanced arrestin mutants and reengineered receptors were used, must be interpreted with caution. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling and Regulation)
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Review

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22 pages, 1441 KiB  
Review
Unveiling the Differences in Signaling and Regulatory Mechanisms between Dopamine D2 and D3 Receptors and Their Impact on Behavioral Sensitization
by Kyeong-Man Kim
Int. J. Mol. Sci. 2023, 24(7), 6742; https://doi.org/10.3390/ijms24076742 - 04 Apr 2023
Cited by 5 | Viewed by 1773
Abstract
Dopamine receptors are classified into five subtypes, with D2R and D3R playing a crucial role in regulating mood, motivation, reward, and movement. Whereas D2R are distributed widely across the brain, including regions responsible for motor functions, D [...] Read more.
Dopamine receptors are classified into five subtypes, with D2R and D3R playing a crucial role in regulating mood, motivation, reward, and movement. Whereas D2R are distributed widely across the brain, including regions responsible for motor functions, D3R are primarily found in specific areas related to cognitive and emotional functions, such as the nucleus accumbens, limbic system, and prefrontal cortex. Despite their high sequence homology and similar signaling pathways, D2R and D3R have distinct regulatory properties involving desensitization, endocytosis, posttranslational modification, and interactions with other cellular components. In vivo, D3R is closely associated with behavioral sensitization, which leads to increased dopaminergic responses. Behavioral sensitization is believed to result from D3R desensitization, which removes the inhibitory effect of D3R on related behaviors. Whereas D2R maintains continuous signal transduction through agonist-induced receptor phosphorylation, arrestin recruitment, and endocytosis, which recycle and resensitize desensitized receptors, D3R rarely undergoes agonist-induced endocytosis and instead is desensitized after repeated agonist exposure. In addition, D3R undergoes more extensive posttranslational modifications, such as glycosylation and palmitoylation, which are needed for its desensitization. Overall, a series of biochemical settings more closely related to D3R could be linked to D3R-mediated behavioral sensitization. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling and Regulation)
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18 pages, 399 KiB  
Review
α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer’s Disease
by Dianne M. Perez
Int. J. Mol. Sci. 2023, 24(4), 4188; https://doi.org/10.3390/ijms24044188 - 20 Feb 2023
Cited by 4 | Viewed by 3629
Abstract
α1-Adrenergic receptors (ARs) are members of the G-Protein Coupled Receptor superfamily and with other related receptors (β and α2), they are involved in regulating the sympathetic nervous system through binding and activation by norepinephrine and epinephrine. Traditionally, α1 [...] Read more.
α1-Adrenergic receptors (ARs) are members of the G-Protein Coupled Receptor superfamily and with other related receptors (β and α2), they are involved in regulating the sympathetic nervous system through binding and activation by norepinephrine and epinephrine. Traditionally, α1-AR antagonists were first used as anti-hypertensives, as α1-AR activation increases vasoconstriction, but they are not a first-line use at present. The current usage of α1-AR antagonists increases urinary flow in benign prostatic hyperplasia. α1-AR agonists are used in septic shock, but the increased blood pressure response limits use for other conditions. However, with the advent of genetic-based animal models of the subtypes, drug design of highly selective ligands, scientists have discovered potentially newer uses for both agonists and antagonists of the α1-AR. In this review, we highlight newer treatment potential for α1A-AR agonists (heart failure, ischemia, and Alzheimer’s disease) and non-selective α1-AR antagonists (COVID-19/SARS, Parkinson’s disease, and posttraumatic stress disorder). While the studies reviewed here are still preclinical in cell lines and rodent disease models or have undergone initial clinical trials, potential therapeutics discussed here should not be used for non-approved conditions. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Signaling and Regulation)
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