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G Protein-Coupled Receptors: Molecular Mechanisms Involved in Receptor Activation and...
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G Protein-Coupled Receptors: Molecular Mechanisms Involved in Receptor Activation and Selectivity

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Physiology and Pathology".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 29441

Special Issue Editors

Dr. Rossella Miele

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Guest Editor
Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Rome, Italy
Interests: G protein-coupled receptor; signal transduction; chemokines; protein-protein interactions; yeast genetic analysis; alternative splicing; transcriptional regulation
Special Issues, Collections and Topics in MDPI journals
Dr. Roberta Lattanzi

E-Mail Website
Guest Editor
Department of Physiology and Pharmacology “Vittorio Erspamer”, University Sapienza, Rome, Italy
Interests: G protein-coupled receptor; chemokines; prokineticins; pain; neuroinflammation; in vivo and in vitro pharmacological analysis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

G Protein-Coupled Receptors (GPCRs) are seven-transmembrane receptors that upon activation predominately transduce their signals through the alpha subunits of heterotrimeric G proteins. GPCRs are present in all cell types and regulate a plethora of physiological functions, whose alterations lead to a pathogenic readout.

Many GPCRs show basal activity that can be modulated by ligands with different efficacy. Full agonists are able to induce the maximal signaling response, while some ligands, known as biased ligands, selectively activate certain receptor-associated pathways at the expense of others. The interaction of GPCRs with extracellular ligands induces an extremely variable response due to the distinct distribution of active conformations of these receptors. Ligand binding and downstream signaling have also been shown to be influenced by the dimeric nature of the receptors.

This Special Issue aims at presenting novel data focused on biochemical, pharmacological, and structural evidence regarding the molecular mechanisms of GPCR activation, whose understanding is crucial to design new highly specific drugs with reduced side effects.

Dr. Rossella Miele
Dr. Roberta Lattanzi
Guest Editors

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Keywords

  • G Protein-Coupled Receptors
  • chemokines
  • dimerization
  • beta-arrestin
  • biased agonist
  • pain
  • inflammation
  • neuroinflammation

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Related Special Issue

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 170 KiB  
Editorial
Special Issue “G Protein-Coupled Receptors: Molecular Mechanisms Involved in Receptor Activation and Selectivity”
by Rossella Miele and Roberta Lattanzi
Life 2023, 13(1), 166; https://doi.org/10.3390/life13010166 - 6 Jan 2023
Viewed by 1319
Abstract
Welcome to the Special Issue of Life entitled “G Protein-Coupled Receptors: Molecular Mechanisms in Receptor Activation and Selectivity” [...] Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Molecular Mechanisms Involved in Receptor Activation and Selectivity)

Research

Jump to: Editorial, Review

17 pages, 1862 KiB  
Article
Evaluation of Pharmacological Rescue of Melanocortin-4 Receptor Nonsense Mutations by Aminoglycoside
by Friederike Höpfner, Sarah Paisdzior, Nanina Reininghaus, Iqra Sohail, Patrick Scheerer, Paolo Annibale, Heike Biebermann and Peter Kühnen
Life 2022, 12(11), 1793; https://doi.org/10.3390/life12111793 - 5 Nov 2022
Cited by 2 | Viewed by 2215
Abstract
The melanocortin-4 receptor (MC4R) is critical for central satiety regulation, therefore presenting a potent target for pharmacological obesity treatment. Melanocortin-4 receptor mutations prevalently cause monogenetic obesity. A possibility of overcoming stop mutations is aminoglycoside-mediated translational readthrough. Promising results were achieved in [...] Read more.
The melanocortin-4 receptor (MC4R) is critical for central satiety regulation, therefore presenting a potent target for pharmacological obesity treatment. Melanocortin-4 receptor mutations prevalently cause monogenetic obesity. A possibility of overcoming stop mutations is aminoglycoside-mediated translational readthrough. Promising results were achieved in COS-7 cells, but data for human cell systems are still missing, so uncertainty surrounds this potential treatment. In transfected HEK-293 cells, we tested whether translational readthrough by aminoglycoside Geneticin combined with high-affinity ligand setmelanotide, which is effective in proopiomelanocortin or leptin receptor deficiency patients, is a treatment option for affected patients. Five MC4R nonsense mutants (W16X, Y35X_D37V, E61X, W258X, Q307X) were investigated. Confocal microscopy and cell surface expression assays revealed the importance of the mutations’ position within the MC4R. N-terminal mutants were marginally expressed independent of Geneticin treatment, whereas mutants with nonsense mutations in transmembrane helix 6 or helix 8 showed wild-type-like expression. For functional analysis, Gs and Gq/11 signaling were measured. N-terminal mutants (W16X, Y35X_D37V) showed no cAMP formation after challenge with alpha-MSH or setmelanotide, irrespective of Geneticin treatment. Similarly, Gs activation was almost impossible in W258X and Q307X with wild-type-like cell surface expression. Results for Gq/11 signaling were comparable. Based on our data, this approach improbably represents a therapeutic option. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Molecular Mechanisms Involved in Receptor Activation and Selectivity)
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11 pages, 1094 KiB  
Article
New Insights on Formyl Peptide Receptor Type 2 Involvement in Nociceptive Processes in the Spinal Cord
by Mariantonella Colucci, Azzurra Stefanucci, Adriano Mollica, Anna Maria Aloisi, Francesco Maione and Stefano Pieretti
Life 2022, 12(4), 500; https://doi.org/10.3390/life12040500 - 29 Mar 2022
Cited by 6 | Viewed by 2104
Abstract
Formyl peptide receptor type 2 (FPR2/ALX) belongs to the formyl peptide receptors (FPRs) family clustered on chromosome 19 and encodes a family of three Class A of G protein-coupled receptors (GPCRs). A short N-terminal region, an NPXXY motif in transmembrane (TM) region 7 [...] Read more.
Formyl peptide receptor type 2 (FPR2/ALX) belongs to the formyl peptide receptors (FPRs) family clustered on chromosome 19 and encodes a family of three Class A of G protein-coupled receptors (GPCRs). A short N-terminal region, an NPXXY motif in transmembrane (TM) region 7 and an E/DRY motif that bridges TM3 and TM6 stabilizing inactive receptor conformations characterize this class of receptors. In recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), FPRs play a crucial role in innate immune responses. FPR2/ALX is highly expressed in myeloid cells, as well as in chondrocytes, fibroblasts, endothelial, epithelial and smooth muscle cells. FPR2/ALX mRNA expression was recently reported in the rat brainstem, spinal cord, thalamus/hypothalamus, cerebral neocortex, hippocampus, cerebellum and striatum. The central nervous system (CNS) distribution of FPR2/ALX suggests important functions in nociception. Thus, the present study was carried out to investigate the possible role of FPR2/ALX in nociception in mice. Intrathecal administration of the formyl peptide receptor type 1 (FPR1) agonist fMLF and the FPR2/ALX agonist BML-111 relieved nociception and these effects were reduced by contemporary administration of the FPR2/ALX antagonist WRW4. Furthermore, measurement of cytokines and brain-derived neurotrophic factor (BDNF) in the spinal cord of neuropathic mice demonstrated that the antinociceptive effects of BML-111 might depend on the reduction in cytokine release and BDNF in the spinal cord. These results suggest a possible role of FPR2/ALX for pain control in the spinal cord. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Molecular Mechanisms Involved in Receptor Activation and Selectivity)
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16 pages, 3402 KiB  
Article
Changes in mGlu5 Receptor Signaling Are Associated with Associative Learning and Memory Extinction in Mice
by Ana Elena Teleuca, Giovanni Sebastiano Alemà, Paola Casolini, Ilaria Barberis, Francesco Ciabattoni, Rosamaria Orlando, Luisa Di Menna, Luisa Iacovelli, Maria Rosaria Scioli, Ferdinando Nicoletti and Anna Rita Zuena
Life 2022, 12(3), 463; https://doi.org/10.3390/life12030463 - 21 Mar 2022
Cited by 4 | Viewed by 2837
Abstract
Using an in vivo method for the assessment of polyphosphoinositide (PI) hydrolysis, we examine whether spatial learning and memory extinction cause changes in mGlu5 metabotropic glutamate receptor signaling in the hippocampus and prefrontal cortex. We use the following five groups of mice: (i) [...] Read more.
Using an in vivo method for the assessment of polyphosphoinositide (PI) hydrolysis, we examine whether spatial learning and memory extinction cause changes in mGlu5 metabotropic glutamate receptor signaling in the hippocampus and prefrontal cortex. We use the following five groups of mice: (i) naive mice; (ii) control mice exposed to the same environment as learner mice; (iii) leaner mice, trained for four days in a water maze; (iv) mice in which memory extinction was induced by six trials without the platform; (v) mice that spontaneously lost memory. The mGlu5 receptor-mediated PI hydrolysis was significantly reduced in the dorsal hippocampus of learner mice as compared to naive and control mice. The mGlu5 receptor signaling was also reduced in the ventral hippocampus and prefrontal cortex of learner mice, but only with respect to naive mice. Memory extinction was associated with a large up-regulation of mGlu5 receptor-mediated PI hydrolysis in the three brain regions and with increases in mGlu5 receptor and phospholipase-Cβ protein levels in the ventral and dorsal hippocampus, respectively. These findings support a role for mGlu5 receptors in mechanisms underlying spatial learning and suggest that mGlu5 receptors are candidate drug targets for disorders in which cognitive functions are impaired or aversive memories are inappropriately retained. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Molecular Mechanisms Involved in Receptor Activation and Selectivity)
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22 pages, 6328 KiB  
Article
In Silico Screening for Pesticide Candidates against the Desert Locust Schistocerca gregaria
by Graham E. Jackson, Gerd Gäde and Heather G. Marco
Life 2022, 12(3), 387; https://doi.org/10.3390/life12030387 - 7 Mar 2022
Cited by 4 | Viewed by 2534
Abstract
Adipokinetic hormone (AKH) is one of the most important metabolic neuropeptides in insects, with actions similar to glucagon in vertebrates. AKH regulates carbohydrate and fat metabolism by mobilizing trehalose and diacylglycerol into circulation from glycogen and triacylglycerol stores, respectively, in the fat body. [...] Read more.
Adipokinetic hormone (AKH) is one of the most important metabolic neuropeptides in insects, with actions similar to glucagon in vertebrates. AKH regulates carbohydrate and fat metabolism by mobilizing trehalose and diacylglycerol into circulation from glycogen and triacylglycerol stores, respectively, in the fat body. The short peptide (8 to 10 amino acids long) exerts its function by binding to a rhodopsin-like G protein-coupled receptor located in the cell membrane of the fat body. The AKH receptor (AKHR) is, thus, a potential target for the development of novel specific (peptide) mimetics to control pest insects, such as locusts, which are feared for their prolific breeding, swarm-forming behavior and voracious appetite. Previously, we proposed a model of the interaction between the three endogenous AKHs of the desert locust, Schistocerca gregaria, and the cognate AKHR (Jackson et al., Peer J. 7, e7514, 2019). In the current study we have performed in silico screening of two databases (NCI Open 2012 library and Zinc20) to identify compounds which may fit the endogenous Schgr-AKH-II binding site on the AKHR of S. gregaria. In all, 354 compounds were found to fit the binding site with glide scores < −8. Using the glide scores and binding energies, 7 docked compounds were selected for molecular dynamic simulation in a phosphatidylcholine membrane. Of these 7 compounds, 4 had binding energies which would allow them to compete with Schgr-AKH-II for the receptor binding site and so are proposed as agonistic ligand candidates. One of the ligands, ZINC000257251537, was tested in a homospecific in vivo biological assay and found to have significant antagonistic activity. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Molecular Mechanisms Involved in Receptor Activation and Selectivity)
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12 pages, 2024 KiB  
Article
Identification and Characterization of a New Splicing Variant of Prokineticin 2
by Roberta Lattanzi, Daniela Maftei, Martina Vincenzi, Maria Rosaria Fullone and Rossella Miele
Life 2022, 12(2), 248; https://doi.org/10.3390/life12020248 - 7 Feb 2022
Cited by 12 | Viewed by 2578
Abstract
Prokineticin 2 (PROK2) is a secreted bioactive peptide that regulates a variety of biological responses via two GPCRs, the prokineticin receptors (PROKRs). The aim of this study was to characterize a new alternatively spliced product of the prok2 gene consisting of four exons. [...] Read more.
Prokineticin 2 (PROK2) is a secreted bioactive peptide that regulates a variety of biological responses via two GPCRs, the prokineticin receptors (PROKRs). The aim of this study was to characterize a new alternatively spliced product of the prok2 gene consisting of four exons. The 40-amino acid peptide, designated PROK2C, is encoded by exon 1 and exon 4, and its expression was detected in the hippocampus and spinal cord of mice. PROK2C was expressed in a heterologous system, Pichia pastoris, and its binding specificity to the amino-terminal regions of PROKR1 and PROKR2 was investigated by GST pull-down experiments. In addition, the introduction of the unnatural amino acid p-benzoyl-L-phenylalanine using amber codon suppression technology demonstrated the role of tryptophan at position 212 of PROKR2 for PROK2C binding by photoactivatable cross-linking. The functional significance of this new isoform was determined in vivo by nociceptive experiments, which showed that PROK2C elicits strong sensitization of peripheral nociceptors to painful stimuli. In order to analyze the induction of PROK2C signal transduction, STAT3 and ERK phosphorylation levels were determined in mammalian CHO cells expressing PROKR1 and PROKR2. Our data show by in vivo and in vitro experiments that PROK2C can bind and activate both prokineticin receptors. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Molecular Mechanisms Involved in Receptor Activation and Selectivity)
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15 pages, 1892 KiB  
Article
Analysis of Signal Transduction Pathways Downstream M2 Receptor Activation: Effects on Schwann Cell Migration and Morphology
by Elisabetta Botticelli, Michael Sebastian Salazar Intriago, Roberta Piovesana and Ada Maria Tata
Life 2022, 12(2), 211; https://doi.org/10.3390/life12020211 - 29 Jan 2022
Cited by 6 | Viewed by 3222
Abstract
Background: Schwann cells (SCs) express cholinergic receptors, suggesting a role of cholinergic signaling in the control of SC proliferation, differentiation and/or myelination. Our previous studies largely demonstrated that the pharmacological activation of the M2 muscarinic receptor subtype caused an inhibition of cell proliferation [...] Read more.
Background: Schwann cells (SCs) express cholinergic receptors, suggesting a role of cholinergic signaling in the control of SC proliferation, differentiation and/or myelination. Our previous studies largely demonstrated that the pharmacological activation of the M2 muscarinic receptor subtype caused an inhibition of cell proliferation and promoted the expression of pro-myelinating differentiation genes. In order to elucidate the molecular signaling activated downstream the M2 receptor activation, in the present study we investigated the signal transduction pathways activated by the M2 orthosteric agonist arecaidine propargyl ester (APE) in SCs. Methods: Using Western blot we analyzed some components of the noncanonical pathways involving β1-arrestin and PI3K/AKT/mTORC1 signaling. A wound healing assay was used to evaluate SC migration. Results: Our results demonstrated that M2 receptor activation negatively modulated the PI3K/Akt/mTORC1 axis, possibly through β1-arrestin downregulation. The involvement of the mTORC1 complex was also supported by the decreased expression of its specific target p-p70 S6KThr389. Then, we also analyzed the expression of p-AMPKαthr172, a negative regulator of myelination that resulted in reduced levels after M2 agonist treatment. The analysis of cell migration and morphology allowed us to demonstrate that M2 receptor activation caused an arrest of SC migration and modified cell morphology probably by the modulation of β1-arrestin/cofilin-1 and PKCα expression, respectively. Conclusions: The data obtained demonstrated that M2 receptor activation in addition to the canonical Gi protein-coupled pathway modulates noncanonical pathways involving the mTORC1 complex and other kinases whose activation may contribute to the inhibition of SC proliferation and migration and address SC differentiation. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Molecular Mechanisms Involved in Receptor Activation and Selectivity)
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12 pages, 2567 KiB  
Article
Pharmacological Characterization of Veldoreotide as a Somatostatin Receptor 4 Agonist
by Pooja Dasgupta, Thomas Gűnther and Stefan Schulz
Life 2021, 11(10), 1075; https://doi.org/10.3390/life11101075 - 12 Oct 2021
Cited by 9 | Viewed by 2172
Abstract
Veldoreotide, a somatostatin analogue, binds to the somatostatin receptors (SSTR) 2, 4, and 5. The current aim was to assess its pharmacological activity as an SSTR4 agonist. G-protein signaling was assessed using a fluorescence-based membrane potential assay in human embryonic kidney 293 (HEK293) [...] Read more.
Veldoreotide, a somatostatin analogue, binds to the somatostatin receptors (SSTR) 2, 4, and 5. The current aim was to assess its pharmacological activity as an SSTR4 agonist. G-protein signaling was assessed using a fluorescence-based membrane potential assay in human embryonic kidney 293 (HEK293) cells stably co-expressing G-protein-coupled inwardly rectifying potassium 2 channels and the individual SSTR2, SSTR4, and SSTR5, and in human BON-1 cells stably expressing these SSTRs. Veldoreotide effects on chromogranin A (CgA) secretion and cell proliferation were examined in BON-1 cells. In HEK293 transfected cells, veldoreotide showed a high efficacy for activating the SSTR4; octreotide and pasireotide had little activity (Emax, 99.5% vs. 27.4% and 52.0%, respectively). Veldoreotide also activated SSTR2 and SSTR5 (Emax, 98.4% and 96.9%, respectively). In BON-1 cells, veldoreotide activated SSTR2, SSTR4, and SSTR5 with high potency and efficacy. CgA secretion was decreased to a greater degree in the BON-1 cells expressing SSTR4 versus the cells expressing SSTR2 and SSTR5 (65.3% vs. 80.3% and 77.6%, respectively). In the BON-1 cells expressing SSTR4, veldoreotide inhibited cell proliferation more than somatostatin SS-14 (71.2% vs. 79.7%) and to a similar extent as the SSTR4 agonist J-2156 in the presence of SSTR2 and SSTR5 antagonists. Veldoreotide is a full agonist of SSTR2, SSTR4, and SSTR5. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Molecular Mechanisms Involved in Receptor Activation and Selectivity)
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13 pages, 757 KiB  
Article
The Association between 5-Hydroxytryptamine Receptor 1B rs13212041 Polymorphism and Trait Anxiety in Chinese Han College Subjects
by Xiaofei Ruan, Suwen Fang, Qi Zheng, Senqing Qi, Yingfang Tian and Wei Ren
Life 2021, 11(9), 882; https://doi.org/10.3390/life11090882 - 27 Aug 2021
Cited by 1 | Viewed by 1863
Abstract
Trait anxiety is a vulnerable personality factor for anxiety and depression. High levels of trait anxiety confer an elevated risk for the development of anxiety and other psychiatric disorders. There is evidence that 5-hydroxytryptamine receptor 1B (5-HT1B) gene polymorphisms play an important role [...] Read more.
Trait anxiety is a vulnerable personality factor for anxiety and depression. High levels of trait anxiety confer an elevated risk for the development of anxiety and other psychiatric disorders. There is evidence that 5-hydroxytryptamine receptor 1B (5-HT1B) gene polymorphisms play an important role in emotional disorders. Genotyping for four single-nucleotide polymorphisms (SNP) (rs11568817, rs130058, rs6297, and rs13212041) was conducted for 388 high trait anxious (HTA) individuals and 463 low traitanxious (LTA) individuals in Chinese Han college subjects. The results showed that the frequencies of the C-allele and TC + CC genotype of rs13212041 in the LTA individuals were higher than that in the HTA individuals (p = 0.025 and p = 0.014, respectively). Both the C-allele and TC + CC genotype were associated with trait anxiety decreasing (OR = 0.771 and OR = 0.71, respectively). Furthermore, different gene model analysis also showed that the C allele was a protective factor for trait anxiety in Chinese Han college subjects. These findings suggest that 5-HT1B rs13212014 may play a role in trait anxiety among China Han college subjects. The rs13212014 polymorphism may be involved in decreasing the risk of trait anxiety. These results also provide a novel insight into the molecular mechanism underlying trait anxiety. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Molecular Mechanisms Involved in Receptor Activation and Selectivity)
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Review

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22 pages, 1280 KiB  
Review
Targeting Chemokines and Chemokine GPCRs to Enhance Strong Opioid Efficacy in Neuropathic Pain
by Martina Vincenzi, Michele Stanislaw Milella, Ginevra D’Ottavio, Daniele Caprioli, Ingrid Reverte and Daniela Maftei
Life 2022, 12(3), 398; https://doi.org/10.3390/life12030398 - 9 Mar 2022
Cited by 7 | Viewed by 3259
Abstract
Neuropathic pain (NP) originates from an injury or disease of the somatosensory nervous system. This heterogeneous origin and the possible association with other pathologies make the management of NP a real challenge. To date, there are no satisfactory treatments for this type of [...] Read more.
Neuropathic pain (NP) originates from an injury or disease of the somatosensory nervous system. This heterogeneous origin and the possible association with other pathologies make the management of NP a real challenge. To date, there are no satisfactory treatments for this type of chronic pain. Even strong opioids, the gold-standard analgesics for nociceptive and cancer pain, display low efficacy and the paradoxical ability to exacerbate pain sensitivity in NP patients. Mounting evidence suggests that chemokine upregulation may be a common mechanism driving NP pathophysiology and chronic opioid use-related consequences (analgesic tolerance and hyperalgesia). Here, we first review preclinical studies on the role of chemokines and chemokine receptors in the development and maintenance of NP. Second, we examine the change in chemokine expression following chronic opioid use and the crosstalk between chemokine and opioid receptors. Then, we examine the effects of inhibiting specific chemokines or chemokine receptors as a strategy to increase opioid efficacy in NP. We conclude that strong opioids, along with drugs that block specific chemokine/chemokine receptor axis, might be the right compromise for a favorable risk/benefit ratio in NP management. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Molecular Mechanisms Involved in Receptor Activation and Selectivity)
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18 pages, 7433 KiB  
Review
Prokineticin-Receptor Network: Mechanisms of Regulation
by Roberta Lattanzi and Rossella Miele
Life 2022, 12(2), 172; https://doi.org/10.3390/life12020172 - 25 Jan 2022
Cited by 17 | Viewed by 3586
Abstract
Prokineticins are a new class of chemokine-like peptides that bind their G protein-coupled receptors, PKR1 and PKR2, and promote chemotaxis and the production of pro-inflammatory cytokines following tissue injury or infection. This review summarizes the major cellular and biochemical mechanisms of prokineticins pathway [...] Read more.
Prokineticins are a new class of chemokine-like peptides that bind their G protein-coupled receptors, PKR1 and PKR2, and promote chemotaxis and the production of pro-inflammatory cytokines following tissue injury or infection. This review summarizes the major cellular and biochemical mechanisms of prokineticins pathway regulation that, like other chemokines, include: genetic polymorphisms; mRNA splice modulation; expression regulation at transcriptional and post-transcriptional levels; prokineticins interactions with cell-surface glycosaminoglycans; PKRs degradation, localization, post-translational modifications and oligomerization; alternative signaling responses; binding to pharmacological inhibitors. Understanding these mechanisms, which together exert substantial biochemical control and greatly enhance the complexity of the prokineticin-receptor network, leads to novel opportunities for therapeutic intervention. In this way, besides targeting prokineticins or their receptors directly, it could be possible to indirectly influence their activity by modulating their expression and localization or blocking the downstream signaling pathways. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors: Molecular Mechanisms Involved in Receptor Activation and Selectivity)
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