Cryptic Dimer Interface and Domain Organization of the Extracellular Region of Metabotropic Glutamate Receptor Subtype 1

Tsuji, Yuji; Shimada, Yoshimi; Takeshita, Tomoko; Kajimura, Naoko; Nomura, Sakashi; Sekiyama, Naohiro; Otomo, Jun; Usukura, Jiro; Nakanishi, Shigetada; Jingami, Hisato

doi:10.1074/jbc.m003226200

Cited by 118 publications

(72 citation statements)

References 35 publications

(27 reference statements)

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“…This indicates that the transmembrane domains and/or extracellular domains (ECDs) encode surfaces that are sufficient for heteromerization, which is in agreement with findings with the COOH-terminally truncated GABA B(1e) splice variant (301). Furthermore, this agrees with data that suggest that other Family 3 GPCRs, e.g., the mGlu1, mGlu5, and CaS receptors, homodimerize in their ECDs (278,286,328).…”

Section: Gaba B Receptor Heteromerizationsupporting

confidence: 80%

Molecular Structure and Physiological Functions of GABA_BReceptors

Bettler

Kaupmann

Mosbacher

et al. 2004

Physiological Reviews

794

720

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GABAB receptors are broadly expressed in the nervous system and have been implicated in a wide variety of neurological and psychiatric disorders. The cloning of the first GABAB receptor cDNAs in 1997 revived interest in these receptors and their potential as therapeutic targets. With the availability of molecular tools, rapid progress was made in our understanding of the GABAB system. This led to the surprising discovery that GABAB receptors need to assemble from distinct subunits to function and provided exciting new insights into the structure of G protein-coupled receptors (GPCRs) in general. As a consequence of this discovery, it is now widely accepted that GPCRs can exist as heterodimers. The cloning of GABAB receptors allowed some important questions in the field to be answered. It is now clear that molecular studies do not support the existence of pharmacologically distinct GABAB receptors, as predicted by work on native receptors. Advances were also made in clarifying the relationship between GABAB receptors and the receptors for γ-hydroxybutyrate, an emerging drug of abuse. There are now the first indications linking GABAB receptor polymorphisms to epilepsy. Significantly, the cloning of GABAB receptors enabled identification of the first allosteric GABAB receptor compounds, which is expected to broaden the spectrum of therapeutic applications. Here we review current concepts on the molecular composition and function of GABAB receptors and discuss ongoing drug-discovery efforts.

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Section: Gaba B Receptor Heteromerizationsupporting

confidence: 80%

Molecular Structure and Physiological Functions of GABA_BReceptors

Bettler

Kaupmann

Mosbacher

et al. 2004

Physiological Reviews

794

720

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“…An additional higher molecular mass EP3-R-immunoreactive band (ϳ125 kDa) was also consistently detected. This band may be the result of SDS-resistant dimerized EP3-R protein as has been reported for other metabotropic receptors (50). Preabsorption of EP3-R antibody with the NH 2 -terminal part of rat EP3-R protein that was used as an antigen (29) eliminated all three of these EP3-R-immunoreactive bands, thus confirming the specificity of this antibody for this EP3-R sequence ( Fig.…”

Section: Resultssupporting

confidence: 57%

Suppression of fever at near term is associated with reduced COX-2 protein expression in rat hypothalamus

Mouihate¹,

Ms²,

Nakamura

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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Suppression of fever at near term is associated with reduced COX-2 protein expression in rat hypothalamus. Am J Physiol Regul Integr Comp Physiol 283: R800-R805, 2002; 10.1152/ ajpregu.00258.2002The fever response is blunted at near term. As the enzyme cyclooxygenase-2 (COX-2) plays a critical role in fever development, we measured its expression in rat hypothalamus during pregnancy and lactation. Western blot analysis revealed a 72-kDa COX-2-immunoreactive band in non-immune-challenged, pregnant rats at day 15 of pregnancy. In contrast, it was almost undetectable at near term and at lactation day 5. COX-2 was significantly induced at the 15th day of pregnancy and at the 5th lactating day after intraperitoneal lipopolysaccharide (50 g/kg). However, this COX-2 induction was significantly reduced at near term compared with values before and after term. The protein levels of the EP3 receptor in the hypothalamus, one of the prostaglandin E 2 (PGE2) receptors suggested to be a key receptor for fever induction, were unaffected throughout the pregnancy and lactation in both non-immune-challenged and lipopolysaccharide-treated rats. These data suggest that suppression of fever at near term is associated with a significantly reduced induction of COX-2 by lipopolysaccharide, resulting in a reduced production of PGE 2. Altered expression of the EP3 receptor does not seem to be involved in this fever refractoriness at near term.cyclooxygenase-2; parturition; lipopolysaccharide; prostaglandin receptor; EP3 receptor FEVER, A MAJOR PART of host defense, is thought to be of beneficial and adaptive value (15). Thus the inability to develop a fever response to pathogens can be detrimental (16). An absent or reduced fever has been observed in pregnant animals at near term (14) and, in some circumstances, is associated with abortion or mortality (23). This febrile refractoriness has been observed in many species, including guinea pig (55), rabbits (28), sheep (14), and rats (7,23,24), and has been observed in response to both peripherally injected pyrogens (14, 23, 55) and, to a lesser extent, to centrally infused prostaglandins (7,24,48). The fact that fever suppression is most dramatic in response to systemically administered LPS suggests that several steps in the cascade of responses to peripherally injected LPS may be affected.In response to bacterial pyrogens such as LPS, immunocompetent cells generate endogenous cytokines, which signal to the central nervous system through either humoral or neuronal pathways (for review, see Ref. 8) to induce expression of cyclooxygenase-2 (COX-2) (6, 22). The activity of this enzyme results in the cyclooxygenation of arachidonic acid and subsequently the production of PGE 2 , which acts largely in the anterior hypothalamus/preoptic area (47). COX-2 is present in basal conditions in the brain (3, 41), but in inflammation, it is induced specifically in the endothelium of brain capillaries (18,25). Levels of COX-2 have been correlated to levels of PGE 2 during LPS-induced fever (54). Because...

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“…Downstream upregulation of the Sox9 transactivation target Col2a1 [39,40] was also confirmed in transplanted oim compared to oim controls (0.11 -0.01$2 -DCt vs. 0.04 -0.01$2 -DCt respectively, P < 0.05) and of the key cartilage matrix component aggrecan [41,42] (4.8 -0.8$2 -DCt vs. 1.1 -0.4$2 -DCt respectively, P < 0.01), found in proliferating chondrocytes. However, expression of the Sox9 target gene Pthrp, which inhibits chondrocyte maturation [43][44][45], was similar in transplanted and nontransplanted oim (5.2 · 10 -4 -0.7 · 10 -4 $2 -DCt vs. 4.8 · 10 -4 -0.5 · 10 -4 $2 -DCt ).…”

Section: Fig 5 Transplanted Oim Have Increased Expression Of Genes mentioning

confidence: 67%

Potential of Human Fetal Chorionic Stem Cells for the Treatment of Osteogenesis Imperfecta

Jones

Moschidou

Abdulrazzak

et al. 2014

Stem Cells and Development

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Osteogenesis imperfecta (OI) is a genetic bone pathology with prenatal onset, characterized by brittle bones in response to abnormal collagen composition. There is presently no cure for OI. We previously showed that human first trimester fetal blood mesenchymal stem cells (MSCs) transplanted into a murine OI model (oim mice) improved the phenotype. However, the clinical use of fetal MSC is constrained by their limited number and low availability. In contrast, human fetal early chorionic stem cells (e-CSC) can be used without ethical restrictions and isolated in high numbers from the placenta during ongoing pregnancy. Here, we show that intraperitoneal injection of e-CSC in oim neonates reduced fractures, increased bone ductility and bone volume (BV), increased the numbers of hypertrophic chondrocytes, and upregulated endogenous genes involved in endochondral and intramembranous ossification. Exogenous cells preferentially homed to long bone epiphyses, expressed osteoblast genes, and produced collagen COL1A2. Together, our data suggest that exogenous cells decrease bone brittleness and BV by directly differentiating to osteoblasts and indirectly stimulating host chondrogenesis and osteogenesis. In conclusion, the placenta is a practical source of stem cells for the treatment of OI.

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Cryptic Dimer Interface and Domain Organization of the Extracellular Region of Metabotropic Glutamate Receptor Subtype 1

Cited by 118 publications

References 35 publications

Molecular Structure and Physiological Functions of GABA_BReceptors

Molecular Structure and Physiological Functions of GABA_BReceptors

Suppression of fever at near term is associated with reduced COX-2 protein expression in rat hypothalamus

Potential of Human Fetal Chorionic Stem Cells for the Treatment of Osteogenesis Imperfecta

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Cryptic Dimer Interface and Domain Organization of the Extracellular Region of Metabotropic Glutamate Receptor Subtype 1

Cited by 118 publications

References 35 publications

Molecular Structure and Physiological Functions of GABABReceptors

Molecular Structure and Physiological Functions of GABABReceptors

Suppression of fever at near term is associated with reduced COX-2 protein expression in rat hypothalamus

Potential of Human Fetal Chorionic Stem Cells for the Treatment of Osteogenesis Imperfecta

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Molecular Structure and Physiological Functions of GABA_BReceptors

Molecular Structure and Physiological Functions of GABA_BReceptors