scholarly journals The G protein-coupled receptor Gpr161 regulates forelimb formation, limb patterning and skeletal morphogenesis in a primary cilium-dependent manner

Development ◽  
2017 ◽  
Vol 145 (1) ◽  
pp. dev154054 ◽  
Author(s):  
Sun-hee Hwang ◽  
Kevin A. White ◽  
Bandarigoda N. Somatilaka ◽  
John M. Shelton ◽  
James A. Richardson ◽  
...  
Keyword(s):  
G Protein ◽  
Primary Cilium ◽  
Dependent Manner ◽  
G Protein Coupled Receptor ◽  
Limb Patterning ◽  
G Protein Coupled

scholarly journals Increase of Anteroventral Periventricular Kisspeptin Neurons and Generation of E2-Induced LH-Surge System in Male Rats Exposed Perinatally to Environmental Dose of Bisphenol-A

Endocrinology ◽  
2011 ◽  
Vol 152 (4) ◽  
pp. 1562-1571 ◽  
Author(s):  
Yinyang Bai ◽  
Fei Chang ◽  
Rong Zhou ◽  
Peng-Peng Jin ◽  
Hirokazu Matsumoto ◽  
...  
Keyword(s):  
Bisphenol A ◽  
G Protein ◽  
Female Rats ◽  
Male Rats ◽  
Perinatal Exposure ◽  
Dependent Manner ◽  
G Protein Coupled Receptor ◽  
Control Male ◽  
Lh Surge ◽  
G Protein Coupled

Abstract Perinatal exposure to environmental levels of bisphenol-A (BPA) impairs sexually dimorphic behaviors in rodents. Kisspeptin neurons in anteroventral periventricular nucleus (AVPV), which plays an important role in the activation of GnRH neurons and the initiation of LH-surge, have been suggested to be sexual dimorphism in rats. This study focused on exploring the influence of a perinatal exposure to an environmental dose of BPA on the development and maturation of male AVPV kisspeptin neurons and hypothalamus-pituitary-gonadal axis. Female rats were injected sc with 2 μg BPA/kg·d from gestation d 10 through lactation d 7. Anatomical and functional changes in AVPV kisspeptin neurons and hypothalamus-pituitary-gonadal axis were examined in prepubertal, pubertal, and adult male rats exposed perinatally to BPA (BPA-rats). Here, we show that in postnatal d (PND)30/50/90 BPA-rats, the number of AVPV kisspeptin-immunoreactive cells was persistently increased in comparison with age-matched control male rats. The number of GnRH-immunoreactive cells in PND30 BPA-rats declined approximately 40% compared with control male rats, whereas that in PND50/90 BPA-rats was increased in a G protein-coupled receptor 54-dependent manner. Estradiol could induce a stable LH-surge in PND90 BPA-rats and control female rats, which was sensitive to the G protein-coupled receptor 54 inhibitor. In PND30/50 BPA-rats, plasma level of LH was higher, but the level of testosterone was lower than control male rats. These findings provide evidence that perinatal exposure to an environmental dose of BPA causes a sustained increase in AVPV kisspeptin neurons in male rats, leading to the generation of estradiol-induced LH-surge system.

scholarly journals Activation of Intracellular Signaling Pathways by the Murine Cytomegalovirus G Protein-Coupled Receptor M33 Occurs via PLC-β/PKC-Dependent and -Independent Mechanisms

2009 ◽  
Vol 83 (16) ◽  
pp. 8141-8152 ◽  
Author(s):  
Joseph D. Sherrill ◽  
Melissa P. Stropes ◽  
Olivia D. Schneider ◽  
Diana E. Koch ◽  
Fabiola M. Bittencourt ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
G Protein ◽  
Intracellular Signaling ◽  
Murine Cytomegalovirus ◽  
Dependent Manner ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

ABSTRACT The presence of numerous G protein-coupled receptor (GPCR) homologs within the herpesvirus genomes suggests an essential role for these genes in viral replication in the infected host. Such is the case for murine cytomegalovirus (MCMV), where deletion of the M33 GPCR or replacement of M33 with a signaling defective mutant has been shown to severely attenuate replication in vivo. In the present study we utilized a genetically altered version of M33 (termed R131A) in combination with pharmacological inhibitors to further characterize the mechanisms by which M33 activates downstream signaling pathways. This R131A mutant of M33 fails to support salivary gland replication in vivo and, as such, is an important tool that can be used to examine the signaling activities of M33. We show that M33 stimulates the transcription factor CREB via heterotrimeric Gq/11 proteins and not through promiscuous coupling of M33 to the Gs pathway. Using inhibitors of signaling molecules downstream of Gq/11, we demonstrate that M33 stimulates CREB transcriptional activity in a phospholipase C-β and protein kinase C (PKC)-dependent manner. Finally, utilizing wild-type and R131A versions of M33, we show that M33-mediated activation of other signaling nodes, including the mitogen-activated protein kinase family member p38α and transcription factor NF-κB, occurs in the absence of Gq/11 and PKC signaling. The results from the present study indicate that M33 utilizes multiple mechanisms to modulate intracellular signaling cascades and suggest that signaling through PLC-β and PKC plays a central role in MCMV pathogenesis in vivo.

scholarly journals Activation of GPR39 With TC-G 1008 Attenuates Neuroinflammation Via SIRT1/PGC-1α/Nrf2 Pathway Post Neonatal Hypoxic-ischemic Injury in Rats

2021 ◽  
Author(s):  
Shucai Xie ◽  
Xili Jiang ◽  
Desislava Met Doycheva ◽  
Hui Shi ◽  
Peng Jin ◽  
...  
Keyword(s):  
G Protein ◽  
Sirtuin 1 ◽  
Neonatal Rat ◽  
Neurological Deficits ◽  
Dependent Manner ◽  
G Protein Coupled Receptor ◽  
Short Term ◽  
Nrf2 Pathway ◽  
G Protein Coupled

Abstract Background: Hypoxic-ischemic encephalopathy (HIE) is a severe anoxic brain injury that leads to premature mortality or long-term disabilities in infants. Neuroinflammation is a vital contributor to the pathogenic cascade post HIE and a mediator to secondary neuronal death. As a plasma membrane G-protein coupled receptor, GPR39, exhibits anti-inflammatory activity in several diseases. This study aimed to explore the neuroprotective function of GPR39 through inhibition of inflammation post hypoxic-ischemic (HI) injury and to elaborate the contribution of sirtuin 1(SIRT1)/ peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α)/ nuclear factor, erythroid 2 like 2(Nrf2) in G protein-coupled receptor 39 (GPR39)-mediated protection.Methods: A total of 206 10-day old Sprague Dawley rat pups were subjected to HIE or sham surgery. TC-G 1008 was administered intranasally at 1h, 25h, 49h, and 73h post HIE induction. SIRT1 inhibitor EX527, GPR39 CRISPR, and PGC-1α CRISPR were administered to elucidate the underlying mechanisms. Brain infarct area, short-term and long-term neurobehavioral tests, Nissl staining, western blot, and immunofluorescence staining were performed post HIE.Results: The expression of GPR39 and pathway-related proteins, SIRT1、PGC-1α and Nrf2 were increased in a time-dependent manner, peaking at 24 h or 48h post HIE. Intranasal administration of TC-G 1008 reduced the percent infarcted area and improved short-term and long-term neurological deficits. Moreover, TC-G 1008 treatment significantly increased the expression of SIRT1, PGC-1α, Nrf2, IL-6, IL-1β, and TNF-α. GPR39 CRISPR EX527 and PGC-1α CRISPR abolished GPR39’s neuroprotective effects post HIE.Conclusions:TC-G 1008 attenuated neuroinflammation in part via the SIRT1/PGC-1α/Nrf2 pathway in a neonatal rat model of HIE. TC-G 1008 may be a novel therapeutic target for treatment post neonatal HIE injury.

scholarly journals Smoothened determines β-arrestin–mediated removal of the G protein–coupled receptor Gpr161 from the primary cilium

2016 ◽  
Vol 212 (7) ◽  
pp. 861-875 ◽  
Author(s):  
Kasturi Pal ◽  
Sun-hee Hwang ◽  
Bandarigoda Somatilaka ◽  
Hemant Badgandi ◽  
Peter K. Jackson ◽  
...  
Keyword(s):  
Membrane Protein ◽  
G Protein ◽  
Primary Cilium ◽  
Protein Composition ◽  
Negative Regulator ◽  
G Protein Coupled Receptor ◽  
New Paradigm ◽  
Subcellular Compartment ◽  
Shh Pathway ◽  
G Protein Coupled

Dynamic changes in membrane protein composition of the primary cilium are central to development and homeostasis, but we know little about mechanisms regulating membrane protein flux. Stimulation of the sonic hedgehog (Shh) pathway in vertebrates results in accumulation and activation of the effector Smoothened within cilia and concomitant disappearance of a negative regulator, the orphan G protein–coupled receptor (GPCR), Gpr161. Here, we describe a two-step process determining removal of Gpr161 from cilia. The first step involves β-arrestin recruitment by the signaling competent receptor, which is facilitated by the GPCR kinase Grk2. An essential factor here is the ciliary trafficking and activation of Smoothened, which by increasing Gpr161–β-arrestin binding promotes Gpr161 removal, both during resting conditions and upon Shh pathway activation. The second step involves clathrin-mediated endocytosis, which functions outside of the ciliary compartment in coordinating Gpr161 removal. Mechanisms determining dynamic compartmentalization of Gpr161 in cilia define a new paradigm for down-regulation of GPCRs during developmental signaling from a specialized subcellular compartment.

scholarly journals Gpr1, a Putative G-Protein-Coupled Receptor, Regulates Morphogenesis and Hypha Formation in the Pathogenic Fungus Candida albicans

2004 ◽  
Vol 3 (4) ◽  
pp. 919-931 ◽  
Author(s):  
Takuya Miwa ◽  
Yukinobu Takagi ◽  
Makiko Shinozaki ◽  
Cheol-Won Yun ◽  
Wiley A. Schell ◽  
...  
Keyword(s):  
Candida Albicans ◽  
G Protein ◽  
Pathogenic Fungus ◽  
Glucose Sensing ◽  
Dependent Manner ◽  
G Protein Coupled Receptor ◽  
Epistasis Analysis ◽  
Hypha Formation ◽  
Mutant Strains ◽  
G Protein Coupled

ABSTRACT In response to various extracellular signals, the morphology of the human fungal pathogen Candida albicans switches from yeast to hypha form. Here, we report that GPR1 encoding a putative G-protein-coupled receptor and GPA2 encoding a Gα subunit are required for hypha formation and morphogenesis in C. albicans. Mutants lacking Gpr1 (gpr1/gpr1) or Gpa2 (gpa2/gpa2) are defective in hypha formation and morphogenesis on solid hypha-inducing media. These phenotypic defects in solid cultures are suppressed by exogenously added dibutyryl-cyclic AMP (dibutyryl-cAMP). Biochemical studies also reveal that GPR1 and GPA2 are required for a glucose-dependent increase in cellular cAMP. An epistasis analysis indicates that Gpr1 functions upstream of Gpa2 in the same signaling pathway, and a two-hybrid assay reveals that the carboxyl-terminal tail of Gpr1 interacts with Gpa2. Moreover, expression levels of HWP1 and ECE1, which are cAMP-dependent hypha-specific genes, are reduced in both mutant strains. These findings support a model that Gpr1, as well as Gpa2, regulates hypha formation and morphogenesis in a cAMP-dependent manner. In contrast, GPR1 and GPA2 are not required for hypha formation in liquid fetal bovine serum (FBS) medium. Furthermore, the gpr1 and the gpa2 mutant strains are fully virulent in a mouse infection. These findings suggest that Gpr1 and Gpa2 are involved in the glucose-sensing machinery that regulates morphogenesis and hypha formation in solid media via a cAMP-dependent mechanism, but they are not required for hypha formation in liquid medium or during invasive candidiasis.

scholarly journals Evidence for a Bacterial Lipopolysaccharide-Recognizing G-Protein-Coupled Receptor in the Bacterial Engulfment by Entamoeba histolytica

2013 ◽  
Vol 12 (11) ◽  
pp. 1433-1438 ◽  
Author(s):  
Matthew T. Brewer ◽  
Prince N. Agbedanu ◽  
Mostafa Zamanian ◽  
Tim A. Day ◽  
Steve A. Carlson
Keyword(s):  
G Protein ◽  
Entamoeba Histolytica ◽  
Drug Target ◽  
Bacterial Flora ◽  
Bacterial Lipopolysaccharide ◽  
Dependent Manner ◽  
G Protein Coupled Receptor ◽  
Concentration Dependent Manner ◽  
Content Type ◽  
G Protein Coupled

ABSTRACT Entamoeba histolytica is the causative agent of amoebic dysentery, a worldwide protozoal disease that results in approximately 100,000 deaths annually. The virulence of E. histolytica may be due to interactions with the host bacterial flora, whereby trophozoites engulf colonic bacteria as a nutrient source. The engulfment process depends on trophozoite recognition of bacterial epitopes that activate phagocytosis pathways. E. histolytica GPCR-1 (EhGPCR-1) was previously recognized as a putative G-protein-coupled receptor (GPCR) used by Entamoeba histolytica during phagocytosis. In the present study, we attempted to characterize EhGPCR-1 by using heterologous GPCR expression in Saccharomyces cerevisiae . We discovered that bacterial lipopolysaccharide (LPS) is an activator of EhGPCR-1 and that LPS stimulates EhGPCR-1 in a concentration-dependent manner. Additionally, we demonstrated that Entamoeba histolytica prefers to engulf bacteria with intact LPS and that this engulfment process is sensitive to suramin, which prevents the interactions of GPCRs and G-proteins. Thus, EhGPCR-1 is an LPS-recognizing GPCR that is a potential drug target for treatment of amoebiasis, especially considering the well-established drug targeting to GPCRs.

Multiple kinases phosphorylate the pancreatic cholecystokinin receptor in an agonist-dependent manner

1993 ◽  
Vol 264 (5) ◽  
pp. G840-G847 ◽  
Author(s):  
L. K. Gates ◽  
C. D. Ulrich ◽  
L. J. Miller
Keyword(s):  
Protein Kinase ◽  
G Protein ◽  
Pancreatic Acinar Cell ◽  
Dependent Manner ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Guanine Nucleotide Binding Protein ◽  
Permeabilized Cells ◽  
High Concentrations ◽  
G Protein Coupled

The cholecystokinin (CCK) receptor on the rat pancreatic acinar cell is a guanine nucleotide-binding protein (G protein)-coupled receptor, which was recently demonstrated to be phosphorylated in response to agonist stimulation (Klueppelberg et al., J. Biol. Chem. 266: 17744-17746, 1991). In this work, we establish that this receptor is phosphorylated in response to a variety of homologous and heterologous secretagogues and that these phosphorylation events represent action by more than one protein kinase. One subgroup of kinases includes one or more isotype of protein kinase C (PKC), and is capable of playing a role in homologous and heterologous desensitization. A second subgroup of kinases that acts on the CCK receptor was defined by its resistance to 10 microM staurosporine, which was shown to inhibit all PKC in these cells. The activity of the second group of kinases was observed only in response to occupation of the CCK receptor by high concentrations of native hormone, raising the possibility of a "receptor-specific kinase." Similar to the prototypical kinase, beta-adrenergic receptor kinase (beta-ARK), this activity was inhibited in permeabilized cells by heparin. Furthermore, like this enzyme activity, beta-ARK was shown to be resistant to staurosporine. Based on its action on a G protein-coupled receptor, its activation at high concentrations of native agonist, and its pattern of inhibition, we believe that the staurosporine-insensitive CCK receptor kinase activity represents either beta-ARK or a closely related member of the receptor-specific kinase enzyme family.

scholarly journals G protein-coupled receptor kinase 2 regulates mitochondrial bioenergetics and impairs myostatin-mediated autophagy in muscle cells

2019 ◽  
Vol 317 (4) ◽  
pp. C674-C686 ◽  
Author(s):  
Leandro Henrique Manfredi ◽  
Joshur Ang ◽  
Nesibe Peker ◽  
Ruben K. Dagda ◽  
Craig McFarlane
Keyword(s):  
Skeletal Muscle ◽  
G Protein ◽  
Mitochondrial Respiration ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Protein Loss ◽  
G Protein Coupled

G protein-coupled receptor kinase 2 (GRK2) is an important protein involved in β-adrenergic receptor desensitization. In addition, studies have shown GRK2 can modulate different metabolic processes in the cell. For instance, GRK2 has been recently shown to promote mitochondrial biogenesis and increase ATP production. However, the role of GRK2 in skeletal muscle and the signaling mechanisms that regulate GRK2 remain poorly understood. Myostatin is a well-known myokine that has been shown to impair mitochondria function. Here, we have assessed the role of myostatin in regulating GRK2 and the subsequent downstream effect of myostatin regulation of GRK2 on mitochondrial respiration in skeletal muscle. Myostatin treatment promoted the loss of GRK2 protein in myoblasts and myotubes in a time- and dose-dependent manner, which we suggest was through enhanced ubiquitin-mediated protein loss, as treatment with proteasome inhibitors partially rescued myostatin-mediated loss of GRK2 protein. To evaluate the effects of GRK2 on mitochondrial respiration, we generated stable myoblast lines that overexpress GRK2. Stable overexpression of GRK2 resulted in increased mitochondrial content and enhanced mitochondrial/oxidative respiration. Interestingly, although overexpression of GRK2 was unable to prevent myostatin-mediated impairment of mitochondrial respiratory function, elevated levels of GRK2 blocked the increased autophagic flux observed following treatment with myostatin. Overall, our data suggest a novel role for GRK2 in regulating mitochondria mass and mitochondrial respiration in skeletal muscle.

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