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16 pages, 2234 KiB

Open AccessArticle

Effect of Sodium Valproate on the Conformational Stability of the Visual G Protein-Coupled Receptor Rhodopsin

by Neda Razzaghi, Pol Fernandez-Gonzalez, Aina Mas-Sanchez, Guillem Vila-Julià, Juan Jesus Perez and Pere Garriga

Molecules 2021, 26(10), 3032; https://doi.org/10.3390/molecules26103032 - 19 May 2021

Cited by 2 | Viewed by 2476

Abstract

Rhodopsin is the G protein-coupled receptor of rod photoreceptor cells that mediates vertebrate vision at low light intensities. Mutations in rhodopsin cause inherited retinal degenerative diseases such as retinitis pigmentosa. Several therapeutic strategies have attempted to address and counteract the deleterious effect of [...] Read more.

Rhodopsin is the G protein-coupled receptor of rod photoreceptor cells that mediates vertebrate vision at low light intensities. Mutations in rhodopsin cause inherited retinal degenerative diseases such as retinitis pigmentosa. Several therapeutic strategies have attempted to address and counteract the deleterious effect of rhodopsin mutations on the conformation and function of this photoreceptor protein, but none has been successful in efficiently preventing retinal degeneration in humans. These approaches include, among others, the use of small molecules, known as pharmacological chaperones, that bind to the receptor stabilizing its proper folded conformation. Valproic acid, in its sodium valproate form, has been used as an anticonvulsant in epileptic patients and in the treatment of several psychiatric disorders. More recently, this compound has been tested as a potential therapeutic agent for the treatment of retinal degeneration associated with retinitis pigmentosa caused by rhodopsin mutations. We now report on the effect of sodium valproate on the conformational stability of heterologously expressed wild-type rhodopsin and a rhodopsin mutant, I307N, which has been shown to be an appropriate model for studying retinal degeneration in mice. We found no sign of enhanced stability for the dark inactive conformation of the I307N mutant. Furthermore, the photoactivated conformation of the mutant appears to be destabilized by sodium valproate as indicated by a faster decay of its active conformation. Therefore, our results support a destabilizing effect of sodium valproate on rhodopsin I307N mutant associated with retinal degeneration. These findings, at the molecular level, agree with recent clinical studies reporting negative effects of sodium valproate on the visual function of retinitis pigmentosa patients. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors)

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17 pages, 3179 KiB

Open AccessArticle

Electron Paramagnetic Resonance Gives Evidence for the Presence of Type 1 Gonadotropin-Releasing Hormone Receptor (GnRH-R) in Subdomains of Lipid Rafts

by Tilen Koklič, Alenka Hrovat, Ramon Guixà-González, Ismael Rodríguez-Espigares, Damaris Navio, Robert Frangež, Matjaž Uršič, Valentina Kubale, Ana Plemenitaš, Jana Selent, Marjeta Šentjurc and Milka Vrecl

Molecules 2021, 26(4), 973; https://doi.org/10.3390/molecules26040973 - 12 Feb 2021

Cited by 1 | Viewed by 2383

Abstract

This study investigated the effect of type 1 gonadotropin releasing hormone receptor (GnRH-R) localization within lipid rafts on the properties of plasma membrane (PM) nanodomain structure. Confocal microscopy revealed colocalization of PM-localized GnRH-R with GM₁-enriched raft-like PM subdomains. Electron paramagnetic resonance [...] Read more.

This study investigated the effect of type 1 gonadotropin releasing hormone receptor (GnRH-R) localization within lipid rafts on the properties of plasma membrane (PM) nanodomain structure. Confocal microscopy revealed colocalization of PM-localized GnRH-R with GM₁-enriched raft-like PM subdomains. Electron paramagnetic resonance spectroscopy (EPR) of a membrane-partitioned spin probe was then used to study PM fluidity of immortalized pituitary gonadotrope cell line αT3-1 and HEK-293 cells stably expressing GnRH-R and compared it with their corresponding controls (αT4 and HEK-293 cells). Computer-assisted interpretation of EPR spectra revealed three modes of spin probe movement reflecting the properties of three types of PM nanodomains. Domains with an intermediate order parameter (domain 2) were the most affected by the presence of the GnRH-Rs, which increased PM ordering (order parameter (S)) and rotational mobility of PM lipids (decreased rotational correlation time (τc)). Depletion of cholesterol by methyl-β-cyclodextrin (methyl-β-CD) inhibited agonist-induced GnRH-R internalization and intracellular Ca²⁺ activity and resulted in an overall reduction in PM order; an observation further supported by molecular dynamics (MD) simulations of model membrane systems. This study provides evidence that GnRH-R PM localization may be related to a subdomain of lipid rafts that has lower PM ordering, suggesting lateral heterogeneity within lipid raft domains. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors)

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18 pages, 2636 KiB

Open AccessArticle

AGS3 and Gα_i3 Are Concomitantly Upregulated as Part of the Spindle Orientation Complex during Differentiation of Human Neural Progenitor Cells

by Jackson L. K. Yip, Maggie M. K. Lee, Crystal C. Y. Leung, Man K. Tse, Annie S. T. Cheung and Yung H. Wong

Molecules 2020, 25(21), 5169; https://doi.org/10.3390/molecules25215169 - 6 Nov 2020

Cited by 2 | Viewed by 3032

Abstract

Adult neurogenesis is modulated by many G_i-coupled receptors but the precise mechanism remains elusive. A key step for maintaining the population of neural stem cells in the adult is asymmetric cell division (ACD), a process which entails the formation of two [...] Read more.

Adult neurogenesis is modulated by many G_i-coupled receptors but the precise mechanism remains elusive. A key step for maintaining the population of neural stem cells in the adult is asymmetric cell division (ACD), a process which entails the formation of two evolutionarily conserved protein complexes that establish the cell polarity and spindle orientation. Since ACD is extremely difficult to monitor in stratified tissues such as the vertebrate brain, we employed human neural progenitor cell lines to examine the regulation of the polarity and spindle orientation complexes during neuronal differentiation. Several components of the spindle orientation complex, but not those of the polarity complex, were upregulated upon differentiation of ENStem-A and ReNcell VM neural progenitor cells. Increased expression of nuclear mitotic apparatus (NuMA), Gα_i subunit, and activators of G protein signaling (AGS3 and LGN) coincided with the appearance of a neuronal marker (β-III tubulin) and the concomitant loss of neural progenitor cell markers (nestin and Sox-2). Co-immunoprecipitation assays demonstrated that both Gα_i3 and NuMA were associated with AGS3 in differentiated ENStem-A cells. Interestingly, AGS3 appeared to preferentially interact with Gα_i3 in ENStem-A cells, and this specificity for Gα_i3 was recapitulated in co-immunoprecipitation experiments using HEK293 cells transiently overexpressing GST-tagged AGS3 and different Gα_i subunits. Moreover, the binding of Gα_i3 to AGS3 was suppressed by GTPγS and pertussis toxin. Disruption of AGS3/Gα_i3 interaction by pertussis toxin indicates that AGS3 may recognize the same site on the Gα subunit as G protein-coupled receptors. Regulatory mechanisms controlling the formation of spindle orientation complex may provide novel means to manipulate ACD which in turn may have an impact on neurogenesis. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors)

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12 pages, 2432 KiB

Open AccessArticle

Design, Synthesis and Characterization of a New Series of Fluorescent Metabotropic Glutamate Receptor Type 5 Negative Allosteric Modulators

by Víctor Fernández-Dueñas, Mingcheng Qian, Josep Argerich, Carolina Amaral, Martijn D.P. Risseeuw, Serge Van Calenbergh and Francisco Ciruela

Molecules 2020, 25(7), 1532; https://doi.org/10.3390/molecules25071532 - 27 Mar 2020

Cited by 2 | Viewed by 2818

Abstract

In recent years, new drug discovery approaches based on novel pharmacological concepts have emerged. Allosteric modulators, for example, target receptors at sites other than the orthosteric binding sites and can modulate agonist-mediated activation. Interestingly, allosteric regulation may allow a fine-tuned regulation of unbalanced [...] Read more.

In recent years, new drug discovery approaches based on novel pharmacological concepts have emerged. Allosteric modulators, for example, target receptors at sites other than the orthosteric binding sites and can modulate agonist-mediated activation. Interestingly, allosteric regulation may allow a fine-tuned regulation of unbalanced neurotransmitter’ systems, thus providing safe and effective treatments for a number of central nervous system diseases. The metabotropic glutamate type 5 receptor (mGlu₅R) has been shown to possess a druggable allosteric binding domain. Accordingly, novel allosteric ligands are being explored in order to finely regulate glutamate neurotransmission, especially in the brain. However, before testing the activity of these new ligands in the clinic or even in animal disease models, it is common to characterize their ability to bind mGlu₅Rs in vitro. Here, we have developed a new series of fluorescent ligands that, when used in a new NanoBRET-based binding assay, will facilitate screening for novel mGlu₅R allosteric modulators. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors)

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Review

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25 pages, 4081 KiB

Open AccessFeature PaperReview

Molecular Modeling of Histamine Receptors—Recent Advances in Drug Discovery

by Pakhuri Mehta, Przemysław Miszta and Sławomir Filipek

Molecules 2021, 26(6), 1778; https://doi.org/10.3390/molecules26061778 - 22 Mar 2021

Cited by 18 | Viewed by 4957

Abstract

The recent developments of fast reliable docking, virtual screening and other algorithms gave rise to discovery of many novel ligands of histamine receptors that could be used for treatment of allergic inflammatory disorders, central nervous system pathologies, pain, cancer and obesity. Furthermore, the [...] Read more.

The recent developments of fast reliable docking, virtual screening and other algorithms gave rise to discovery of many novel ligands of histamine receptors that could be used for treatment of allergic inflammatory disorders, central nervous system pathologies, pain, cancer and obesity. Furthermore, the pharmacological profiles of ligands clearly indicate that these receptors may be considered as targets not only for selective but also for multi-target drugs that could be used for treatment of complex disorders such as Alzheimer’s disease. Therefore, analysis of protein-ligand recognition in the binding site of histamine receptors and also other molecular targets has become a valuable tool in drug design toolkit. This review covers the period 2014–2020 in the field of theoretical investigations of histamine receptors mostly based on molecular modeling as well as the experimental characterization of novel ligands of these receptors. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors)

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17 pages, 7566 KiB

Open AccessReview

Structural Insights into Ligand—Receptor Interactions Involved in Biased Agonism of G-Protein Coupled Receptors

by Krzysztof Jóźwiak and Anita Płazińska

Molecules 2021, 26(4), 851; https://doi.org/10.3390/molecules26040851 - 6 Feb 2021

Cited by 7 | Viewed by 3511

Abstract

G protein-coupled receptors (GPCRs) are versatile signaling proteins that mediate complex cellular responses to hormones and neurotransmitters. Ligand directed signaling is observed when agonists, upon binding to the same receptor, trigger significantly different configuration of intracellular events. The current work reviews the structurally [...] Read more.

G protein-coupled receptors (GPCRs) are versatile signaling proteins that mediate complex cellular responses to hormones and neurotransmitters. Ligand directed signaling is observed when agonists, upon binding to the same receptor, trigger significantly different configuration of intracellular events. The current work reviews the structurally defined ligand – receptor interactions that can be related to specific molecular mechanisms of ligand directed signaling across different receptors belonging to class A of GPCRs. Recent advances in GPCR structural biology allow for mapping receptors’ binding sites with residues particularly important in recognition of ligands’ structural features that are responsible for biased signaling. Various studies show particular role of specific residues lining the extended ligand binding domains, biased agonists may alternatively affect their interhelical interactions and flexibility what can be translated into intracellular loop rearrangements. Studies on opioid and angiotensin receptors indicate importance of residues located deeper within the binding cavity and direct interactions with receptor residues linking the ortosteric ligand binding site with the intracellular transducer binding domain. Collection of results across different receptors may suggest elements of common molecular mechanisms which are responsible for passing alternative signals from biased agonists. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors)

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23 pages, 3527 KiB

Open AccessReview

Methods for Studying Endocytotic Pathways of Herpesvirus Encoded G Protein-Coupled Receptors

by Maša Mavri, Katja Spiess, Mette Marie Rosenkilde, Catrin Sian Rutland, Milka Vrecl and Valentina Kubale

Molecules 2020, 25(23), 5710; https://doi.org/10.3390/molecules25235710 - 3 Dec 2020

Cited by 5 | Viewed by 3391

Abstract

Endocytosis is a fundamental process involved in trafficking of various extracellular and transmembrane molecules from the cell surface to its interior. This enables cells to communicate and respond to external environments, maintain cellular homeostasis, and transduce signals. G protein-coupled receptors (GPCRs) constitute a [...] Read more.

Endocytosis is a fundamental process involved in trafficking of various extracellular and transmembrane molecules from the cell surface to its interior. This enables cells to communicate and respond to external environments, maintain cellular homeostasis, and transduce signals. G protein-coupled receptors (GPCRs) constitute a family of receptors with seven transmembrane alpha-helical domains (7TM receptors) expressed at the cell surface, where they regulate physiological and pathological cellular processes. Several herpesviruses encode receptors (vGPCRs) which benefits the virus by avoiding host immune surveillance, supporting viral dissemination, and thereby establishing widespread and lifelong infection, processes where receptor signaling and/or endocytosis seem central. vGPCRs are rising as potential drug targets as exemplified by the cytomegalovirus-encoded receptor US28, where its constitutive internalization has been exploited for selective drug delivery in virus infected cells. Therefore, studying GPCR trafficking is of great importance. This review provides an overview of the current knowledge of endocytic and cell localization properties of vGPCRs and methodological approaches used for studying receptor internalization. Using such novel approaches, we show constitutive internalization of the BILF1 receptor from human and porcine γ-1 herpesviruses and present motifs from the eukaryotic linear motif (ELM) resources with importance for vGPCR endocytosis. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors)

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14 pages, 2686 KiB

Open AccessFeature PaperReview

Natural Compounds as Guides for the Discovery of Drugs Targeting G-Protein-Coupled Receptors

by Joan Serrano-Marín, Irene Reyes-Resina, Eva Martínez-Pinilla, Gemma Navarro and Rafael Franco

Molecules 2020, 25(21), 5060; https://doi.org/10.3390/molecules25215060 - 30 Oct 2020

Cited by 10 | Viewed by 4710

Abstract

G protein-coupled receptors (GPCRs), which constitute the most populous family of the human proteome, are the target of 35–45% of approved therapeutic drugs. This review focuses on natural products (excluding peptides) that target GPCRs. Natural compounds identified so far as agonists, antagonists or [...] Read more.

G protein-coupled receptors (GPCRs), which constitute the most populous family of the human proteome, are the target of 35–45% of approved therapeutic drugs. This review focuses on natural products (excluding peptides) that target GPCRs. Natural compounds identified so far as agonists, antagonists or allosteric modulators of GPCRs have been found in all groups of existing living beings according to Whittaker’s Five Kingdom Classification, i.e., bacteria (monera), fungi, protoctists, plants and animals. Terpenoids, alkaloids and flavonoids are the most common chemical structures that target GPCRs whose endogenous ligands range from lipids to epinephrine, from molecules that activate taste receptors to molecules that activate smell receptors. Virtually all of the compounds whose formula is displayed in this review are pharmacophores with potential for drug discovery; furthermore, they are expected to help expand the number of GPCRs that can be considered as therapeutic targets. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors)

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