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Advanced Researches in G-Protein-Coupled Receptors (GPCRs) and Their Closely Related...
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Advanced Researches in G-Protein-Coupled Receptors (GPCRs) and Their Closely Related Functional Proteins

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (5 November 2022) | Viewed by 17621

Special Issue Editor

Prof. Dr. Yasuhito Uezono

E-Mail Website
Guest Editor
Department of Pain Control Research, The Jikei University School of Medicine, Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan
Interests: G protein-coupled receptors; beta-arrestins; G protein-coupled kinases (GRKs); heterodimerized GPCRs; signal biased GPCR ligands

Special Issue Information

Dear Colleagues,

G-protein-coupled receptors (GPCRs) are a large diverse family of cell surface signaling receptors, implicated in various normal physiologies and diseases. These receptors modulate the key pathways in various systems and participate in many different cellular processes, which are involved in the regulation of human diseases. Thus, GPCRs are potential therapeutic targets for a range of diseases.  

This Special Issue focuses on the roles of GPCRs and closely related functional proteins such as b-arrestins and G-protein-coupled kinases (GRKs), as well as their diverse signal transduction pathways in various diseases. The scope of these topics includes, but is not limited to, the mechanisms underlying GPCR signaling in the regulation of the pathogenesis of diseases, GPCRs and their diverse downstream signaling pathways in diseases, the modulation of diseases by GPCRs, and host responses to potential therapeutic strategies targeting GPCRs.

Prof. Dr. Yasuhito Uezono
Guest Editor

Manuscript Submission Information

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Keywords

  • G-protein-coupled receptors
  • beta-arrestins
  • G-protein-coupled kinases (GRKs)
  • heterodimerized GPCRs
  • signal biased GPCR ligands

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Published Papers (5 papers)

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Research

17 pages, 2716 KiB  
Article
Spinal Astrocyte-Neuron Lactate Shuttle Contributes to the Pituitary Adenylate Cyclase-Activating Polypeptide/PAC1 Receptor-Induced Nociceptive Behaviors in Mice
by Yuki Kambe, Masafumi Youkai, Kohei Hashiguchi, Yoshimune Sameshima, Ichiro Takasaki, Atsuro Miyata and Takashi Kurihara
Biomolecules 2022, 12(12), 1859; https://doi.org/10.3390/biom12121859 - 12 Dec 2022
Cited by 2 | Viewed by 1927
Abstract
We have previously shown that spinal pituitary adenylate cyclase-activating polypeptide (PACAP)/PACAP type 1 (PAC1) receptor signaling triggered long-lasting nociceptive behaviors through astroglial activation in mice. Since astrocyte-neuron lactate shuttle (ANLS) could be essential for long-term synaptic facilitation, we aimed to elucidate a possible [...] Read more.
We have previously shown that spinal pituitary adenylate cyclase-activating polypeptide (PACAP)/PACAP type 1 (PAC1) receptor signaling triggered long-lasting nociceptive behaviors through astroglial activation in mice. Since astrocyte-neuron lactate shuttle (ANLS) could be essential for long-term synaptic facilitation, we aimed to elucidate a possible involvement of spinal ANLS in the development of the PACAP/PAC1 receptor-induced nociceptive behaviors. A single intrathecal administration of PACAP induced short-term spontaneous aversive behaviors, followed by long-lasting mechanical allodynia in mice. These nociceptive behaviors were inhibited by 1,4-dideoxy-1,4-imino-d-arabinitol (DAB), an inhibitor of glycogenolysis, and this inhibition was reversed by simultaneous L-lactate application. In the cultured spinal astrocytes, the PACAP-evoked glycogenolysis and L-lactate secretion were inhibited by DAB. In addition, a protein kinase C (PKC) inhibitor attenuated the PACAP-induced nociceptive behaviors as well as the PACAP-evoked glycogenolysis and L-lactate secretion. Finally, an inhibitor for the monocarboxylate transporters blocked the L-lactate secretion from the spinal astrocytes and inhibited the PACAP- and spinal nerve ligation-induced nociceptive behaviors. These results suggested that spinal PAC1 receptor-PKC-ANLS signaling contributed to the PACAP-induced nociceptive behaviors. This signaling system could be involved in the peripheral nerve injury-induced pain-like behaviors. Full article
(This article belongs to the Special Issue Advanced Researches in G-Protein-Coupled Receptors (GPCRs) and Their Closely Related Functional Proteins)
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13 pages, 1956 KiB  
Article
Receptor Transporter Protein 4 (RTP4) in the Hypothalamus Is Involved in the Development of Antinociceptive Tolerance to Morphine
by Wakako Fujita, Hitoshi Uchida, Masashi Kawanishi, Yusuke Kuroiwa, Manabu Abe and Kenji Sakimura
Biomolecules 2022, 12(10), 1471; https://doi.org/10.3390/biom12101471 - 13 Oct 2022
Cited by 5 | Viewed by 2007
Abstract
Receptor transporter protein 4 (RTP4), one of the receptor chaperone proteins, contributes to the maturation and membrane trafficking of opioid receptor heteromers consisting of mu (MOPr) and delta (DOPr) opioid receptors (MOPr-DOPr). Although MOPr-DOPr is known to mediate the development of morphine tolerance, [...] Read more.
Receptor transporter protein 4 (RTP4), one of the receptor chaperone proteins, contributes to the maturation and membrane trafficking of opioid receptor heteromers consisting of mu (MOPr) and delta (DOPr) opioid receptors (MOPr-DOPr). Although MOPr-DOPr is known to mediate the development of morphine tolerance, the extent to which RTP4 plays a role in this process has not been elucidated. Given that RTP4 can be upregulated by repeated administration of morphine, especially in the hypothalamus, here we investigated the effect of hypothalamus-selective ablation of RTP4 on the development of antinociceptive tolerance to morphine. In this study, we generated RTP4flox mice and selectively knocked-out RTP4 using local injection of adeno-associated virus expressing Cre recombinase (AAV-Cre) into the hypothalamus. The AAV-Cre injection partially, but significantly, decreased the level of RTP4 expression, and suppressed the development of antinociceptive tolerance to morphine. Next, we examined the mechanism of regulation of RTP4 and found that, in neuronal cells, Rtp4 induction is via Gi and MAPK activation, while, in microglial cells, the induction is via Toll-like receptor 4. Together, these studies highlight the role of MOR activity in regulating RTP4, which, in turn, plays an important role in modulating morphine effects in vivo. Full article
(This article belongs to the Special Issue Advanced Researches in G-Protein-Coupled Receptors (GPCRs) and Their Closely Related Functional Proteins)
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9 pages, 830 KiB  
Article
Plasma Clearance of Intravenously Infused Adrenomedullin in Rats with Acute Renal Failure
by Hiroshi Hosoda, Tsutomu Nakamura and Fumiki Yoshihara
Biomolecules 2022, 12(9), 1281; https://doi.org/10.3390/biom12091281 - 11 Sep 2022
Cited by 1 | Viewed by 2026
Abstract
Plasma adrenomedullin concentrations are reportedly elevated in patients with renal failure; however, the underlying mechanism is unclear. In this study, we investigated the plasma clearance of synthetic human adrenomedullin (AM) in two models of rats with renal dysfunction; one was induced by subcutaneous [...] Read more.
Plasma adrenomedullin concentrations are reportedly elevated in patients with renal failure; however, the underlying mechanism is unclear. In this study, we investigated the plasma clearance of synthetic human adrenomedullin (AM) in two models of rats with renal dysfunction; one was induced by subcutaneous injection of mercury chloride (RD-Ag) and the other by completely blocking bilateral renal blood flow (RD-Bl). Sixty minutes after starting intravenous AM infusion, AM levels in RD-Ag, RD-Bl, and rats with normal renal function (NF) were still increased slightly; however, plasma AM levels in RD-Ag rats were approximately three times as high as in RD-Bl and NF rats. Plasma AM disappearance after the end of treatment was similar among the three groups. Pharmacokinetic analysis revealed that elevated plasma AM in RD-Ag rats may be caused by a reduced volume of distribution. The adrenomedullin functional receptor is composed of heterodimers, including GPCR, CLR (calcitonin receptor-like receptor, CALCRL), and the single transmembrane proteins, RAMP2 or RAMP3 (receptor activity modifying protein). Calcrl expression was downregulated in the lungs and kidneys of RD-Ag rats. Furthermore, the plasma concentration of exogenous AM was elevated in mice deficient in vascular endothelium-specific Ramp2. These results suggest that decreased plasma AM clearance in RD-Ag is not due to impaired renal excretion but to a decreased volume of distribution caused by a reduction in adrenomedullin receptors. Full article
(This article belongs to the Special Issue Advanced Researches in G-Protein-Coupled Receptors (GPCRs) and Their Closely Related Functional Proteins)
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17 pages, 3607 KiB  
Article
Public Transcriptomic Data Meta-Analysis Demonstrates TAAR6 Expression in the Mental Disorder-Related Brain Areas in Human and Mouse Brain
by Anastasia N. Vaganova, Nataliia V. Katolikova, Ramilya Z. Murtazina, Savelii R. Kuvarzin and Raul R. Gainetdinov
Biomolecules 2022, 12(9), 1259; https://doi.org/10.3390/biom12091259 - 7 Sep 2022
Cited by 4 | Viewed by 2626
Abstract
G protein-coupled trace amine-associated receptors (TAAR) recognize different classes of amine compounds, including trace amines or other exogenous and endogenous molecules. Yet, most members of the TAAR family (TAAR2-TAAR9) are considered olfactory receptors involved in sensing innate odors. In this study, TAAR6 mRNA [...] Read more.
G protein-coupled trace amine-associated receptors (TAAR) recognize different classes of amine compounds, including trace amines or other exogenous and endogenous molecules. Yet, most members of the TAAR family (TAAR2-TAAR9) are considered olfactory receptors involved in sensing innate odors. In this study, TAAR6 mRNA expression was evaluated in the brain transcriptomic datasets available in the GEO, Allen Brain Atlas, and GTEx databases. Transcriptomic data analysis demonstrated ubiquitous weak TAAR6 mRNA expression in the brain, especially in the prefrontal cortex and nucleus accumbens. RNA sequencing of isolated cells from the nucleus accumbens showed that the expression of TAAR6 in some cell populations may be more pronounced than in whole-tissue samples. Curiously, in D1 and D2 dopamine receptor-expressing medium spiny GABAergic neurons of the nucleus accumbens, TAAR6 expression was co-regulated with genes involved in G protein-coupled receptor signaling. However, in cholinergic interneurons of the nucleus accumbens, TAAR6 expression was not associated with the activation of any specific biological process. Finally, TAAR6 expression in the mouse prefrontal cortex was validated experimentally by RT-PCR analysis. These data demonstrated that TAAR6 is expressed at low levels in the human and mouse brain, particularly in limbic structures involved in the pathogenesis of mental disorders, and thus might represent a new pharmacotherapeutic target. Full article
(This article belongs to the Special Issue Advanced Researches in G-Protein-Coupled Receptors (GPCRs) and Their Closely Related Functional Proteins)
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16 pages, 2153 KiB  
Article
Ketamine Improves Desensitization of µ-Opioid Receptors Induced by Repeated Treatment with Fentanyl but Not with Morphine
by Yusuke Mizobuchi, Kanako Miyano, Sei Manabe, Eiko Uezono, Akane Komatsu, Yui Kuroda, Miki Nonaka, Yoshikazu Matsuoka, Tetsufumi Sato, Yasuhito Uezono and Hiroshi Morimatsu
Biomolecules 2022, 12(3), 426; https://doi.org/10.3390/biom12030426 - 10 Mar 2022
Cited by 5 | Viewed by 8263
Abstract
The issue of tolerance to continuous or repeated administration of opioids should be addressed. The ability of ketamine to improve opioid tolerance has been reported in clinical studies, and its mechanism of tolerance may involve improved desensitization of μ-opioid receptors (MORs). We measured [...] Read more.
The issue of tolerance to continuous or repeated administration of opioids should be addressed. The ability of ketamine to improve opioid tolerance has been reported in clinical studies, and its mechanism of tolerance may involve improved desensitization of μ-opioid receptors (MORs). We measured changes in MOR activity and intracellular signaling induced by repeated fentanyl and morphine administration and investigated the effects of ketamine on these changes with human embryonic kidney 293 cells expressing MOR using the CellKey™, cADDis cyclic adenosine monophosphate, and PathHunter® β-arrestin recruitment assays. Repeated administration of fentanyl or morphine suppressed the second MOR responses. Administration of ketamine before a second application of opioids within clinical concentrations improved acute desensitization and enhanced β-arrestin recruitment elicited by fentanyl but not by morphine. The effects of ketamine on fentanyl were suppressed by co-treatment with an inhibitor of G-protein-coupled receptor kinase (GRK). Ketamine may potentially reduce fentanyl tolerance but not that of morphine through modulation of GRK-mediated pathways, possibly changing the conformational changes of β-arrestin to MOR. Full article
(This article belongs to the Special Issue Advanced Researches in G-Protein-Coupled Receptors (GPCRs) and Their Closely Related Functional Proteins)
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