Metabotropni glutamatni receptor 2

Metabotropni glutamatni receptor 2‎‎
Metabotropni glutamatni receptor 2‎‎
Identifikatori
Simboli	GRM2; GLUR2; GPRC1B; MGLUR2; mGlu2
Vanjski ID	OMIM: 604099 MGI: 1351339 HomoloGene: 20229 IUPHAR: mGlu2 GeneCards: GRM2 Gene
Ontologija gena
Molekularna funkcija	• Aktivnost metabotropnog glutamatnog receptora grupe II; • aktivnost prenosnika signala; • receptorska aktivnost; • aktivnost G protein spregnutog receptora; • aktivnost regulatora kalcijumskog kanala; • aktivnost glutamatnog receptora;
Celularna komponenta	• intracelularni; • ćelijska membrana; • integralno sa ćelijskom membranom; • akson; • presinaptička membrana;
Biološki proces	• signalni put G protein spregnutog receptora; • aktivnost negativne regulacije adenilat ciklaze; • inhibicija aktivnosti adenilat ciklaze signalnim putem G protein spregnutog glutamatnog receptora; • sinaptička transmisija; • glutamatna sekrecija;
Pregled RNK izražavanja
	podaci
Ortolozi
Vrsta	Čovek
Entrez	2912
Ensembl	ENSG00000164082
UniProt	Q14416
RefSeq (mRNA)	NM_000839.3
RefSeq (protein)	NP_000830.2
Lokacija (UCSC)	Chr 3:; 51.74 - 51.75 Mb
PubMed pretraga	[1]

Metabotropni glutamatni receptor 2 je protein je protein koji je kod ljudi kodiran GRM2 genom.^[1]^[2]

L-glutamat je jedan od glavnih ekscitatornih neurotransmitera u centralnom nervnom sistemu i aktivira jonotropne i metabotropne glutamatne receptore. Glutamatergična neurotransmisija učestvuje u većini aspekata normalnih moždanih funkcija i može da bude poremećena u slučaju neuropatoloških poremećaja. Metabotropni glutamatni receptori su familija G protein spregnutih receptora, koji se dele u 3 grupe na bazi homologije sekvenci, signalno transdukcionih mehanizama, i farmakoloških svojstava. Grupa I obuhvata GRM1 i GRM5 i ti receptori aktiviraju fosfolipazu C. Grupa II uključuje GRM2 i GRM3, dok su u grupi III GRM4, GRM6, GRM7 i GRM8. Receptori grupe II i III su vezani za inhibiciju kaskade cikličnog AMP-a, ali se razlikuju u njihovim selektivnostima za agoniste.^[2]

Ligandi

PAM

Razvoj podtip 2 selektivnih pozitivnih alosternih modulatora (PAM) je doživeo stabilan napredak zadnjih godina.^[3] mGluR2 potencijacija je nov pristup tretiranju šizofrenije.^[4]

Visoko selektivni mGluR2 PAM (2010)^[5], BINA analog

GSK1331258^[6]
Imidazo[1,2-a]piridini^[7]
3-Aril-5-fenoksimetil-1,3-oksazolidin-2-oni^[8]
3-(Imidazolil metil)-3-aza-biciklo[3.1.0]heksan-6-il)metil etri: potentni, oralno stabilni^[9]
BINA:^[10]^[11] potentan, umereni ago-alosterni modulator sa robustno in-vivo aktivnošću.
LY487379:^[12]^[13]^[14] bez ortosterne aktivnosti; zajedno sa srodnim 3-piridilmetilsulfonamidima^[15]^[16] je prvi objavljeni selektivni potencijator za podtip 2 (2003).

Vidi još

Metabotropni glutamatni receptor

Reference

^ Flor PJ, Lindauer K, Puttner I, Ruegg D, Lukic S, Knopfel T, Kuhn R (1995). „Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 2”. Eur J Neurosci. 7 (4): 622—9. PMID 7620613. doi:10.1111/j.1460-9568.1995.tb00666.x.
^ ^а ^б „Entrez Gene: GRM2 glutamate receptor, metabotropic 2”.
^ Fraley ME (2009). „Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia”. Expert Opin Ther Pat. 19 (9): 1259—75. PMID 19552508. doi:10.1517/13543770903045009.
^ Conn PJ, Jones CK (2009). „Promise of mGluR2/3 activators in psychiatry”. Neuropsychopharmacology. 34 (1): 248—9. PMC 2907744  . PMID 19079073. doi:10.1038/npp.2008.156.
^ Dhanya RP; Sidique S; Sheffler DJ; et al. (2011). „Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats”. J. Med. Chem. 54 (1): 342—53. PMC 3071440  . PMID 21155570. doi:10.1021/jm1012165.
^ D'Alessandro PL, Corti C, Roth A, Ugolini A, Sava A, Montanari D, Bianchi F, Garland SL, Powney B, Koppe EL, Rocheville M, Osborne G, Perez P, de la Fuente J, De Los Frailes M, Smith PW, Branch C, Nash D, Watson SP (2010). „The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2”. Bioorg. Med. Chem. Lett. 20 (2): 759—62. PMID 20005096. doi:10.1016/j.bmcl.2009.11.032.
^ Tresadern G, Cid JM, Macdonald GJ, Vega JA, de Lucas AI, García A, Matesanz E, Linares ML, Oehlrich D, Lavreysen H, Biesmans I, Trabanco AA (2010). „Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor”. Bioorg. Med. Chem. Lett. 20 (1): 175—9. PMID 19932615. doi:10.1016/j.bmcl.2009.11.008.
^ EJ Brnardic 2010
^ Zhang L; Rogers BN; Duplantier AJ; et al. (2008). „3-(Imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers: a novel series of mGluR2 positive allosteric modulators”. Bioorganic & Medicinal Chemistry Letters. 18 (20): 5493—6. PMID 18812259. doi:10.1016/j.bmcl.2008.09.026.
^ Galici R; Jones CK; Hemstapat K; et al. (2006). „Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice”. J. Pharmacol. Exp. Ther. 318 (1): 173—85. PMID 16608916. doi:10.1124/jpet.106.102046.
^ Bonnefous C; Vernier JM; Hutchinson JH; et al. (2005). „Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor”. Bioorg. Med. Chem. Lett. 15 (19): 4354—8. PMID 16046122. doi:10.1016/j.bmcl.2005.06.062.
^ Johnson MP; Baez M; Jagdmann GE; et al. (2003). „Discovery of allosteric potentiators for the metabotropic glutamate 2 receptor: synthesis and subtype selectivity of N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2- trifluoroethylsulfonyl)pyrid-3-ylmethylamine”. J. Med. Chem. 46 (15): 3189—92. PMID 12852748. doi:10.1021/jm034015u.
^ Johnson MP; Barda D; Britton TC; et al. (2005). „Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s)”. Psychopharmacology (Berl.). 179 (1): 271—83. PMID 15717213. doi:10.1007/s00213-004-2099-9.
^ Schaffhauser H; Rowe BA; Morales S; et al. (2003). „Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2”. Mol. Pharmacol. 64 (4): 798—810. PMID 14500736. doi:10.1124/mol.64.4.798.
^ Barda DA, Wang ZQ, Britton TC, et al. (2004). „SAR study of a subtype selective allosteric potentiator of metabotropic glutamate 2 receptor, N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide”. Bioorg. Med. Chem. Lett. 14 (12): 3099—102. PMID 15149652. doi:10.1016/j.bmcl.2004.04.017.
^ Pinkerton AB; Vernier JM; Schaffhauser H; et al. (2004). „Phenyl-tetrazolyl acetophenones: discovery of positive allosteric potentiatiors for the metabotropic glutamate 2 receptor”. J. Med. Chem. 47 (18): 4595—9. PMID 15317469. doi:10.1021/jm040088h.

Literatura

Scherer SW; Duvoisin RM; Kuhn R; et al. (1997). „Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q”. Genomics. 31 (2): 230—3. PMID 8824806. doi:10.1006/geno.1996.0036.
Gomeza J; Mary S; Brabet I; et al. (1996). „Coupling of metabotropic glutamate receptors 2 and 4 to G alpha 15, G alpha 16, and chimeric G alpha q/i proteins: characterization of new antagonists”. Mol. Pharmacol. 50 (4): 923—30. PMID 8863838.
Snow BE; Hall RA; Krumins AM; et al. (1998). „GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain”. J. Biol. Chem. 273 (28): 17749—55. PMID 9651375. doi:10.1074/jbc.273.28.17749.
Malherbe P; Knoflach F; Broger C; et al. (2001). „Identification of essential residues involved in the glutamate binding pocket of the group II metabotropic glutamate receptor”. Mol. Pharmacol. 60 (5): 944—54. PMID 11641422.
Martí SB, Cichon S, Propping P, Nöthen M (2002). „Human metabotropic glutamate receptor 2 gene (GRM2): chromosomal sublocalization (3p21.1-p21.2) and genomic organization”. Am. J. Med. Genet. 114 (1): 12—4. PMID 11840499. doi:10.1002/ajmg.1622.
Krampfl K; Schlesinger F; Zörner A; et al. (2002). „Control of kinetic properties of GluR2 flop AMPA-type channels: impact of R/G nuclear editing”. Eur. J. Neurosci. 15 (1): 51—62. PMID 11860506. doi:10.1046/j.0953-816x.2001.01841.x.
Dietrich D; Kral T; Clusmann H; et al. (2002). „Presynaptic group II metabotropic glutamate receptors reduce stimulated and spontaneous transmitter release in human dentate gyrus”. Neuropharmacology. 42 (3): 297—305. PMID 11897108. doi:10.1016/S0028-3908(01)00193-9.
Strausberg RL; Feingold EA; Grouse LH; et al. (2003). „Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences”. Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899—903. PMC 139241  . PMID 12477932. doi:10.1073/pnas.242603899.
Kuwabara T; Hsieh J; Nakashima K; et al. (2004). „A small modulatory dsRNA specifies the fate of adult neural stem cells”. Cell. 116 (6): 779—93. PMID 15035981. doi:10.1016/S0092-8674(04)00248-X.
Tang FR; Chia SC; Chen PM; et al. (2004). „Metabotropic glutamate receptor 2/3 in the hippocampus of patients with mesial temporal lobe epilepsy, and of rats and mice after pilocarpine-induced status epilepticus”. Epilepsy Res. 59 (2–3): 167—80. PMID 15246118. doi:10.1016/j.eplepsyres.2004.04.002.
Anneser JM; Chahli C; Ince PG; et al. (2004). „Glial proliferation and metabotropic glutamate receptor expression in amyotrophic lateral sclerosis”. J. Neuropathol. Exp. Neurol. 63 (8): 831—40. PMID 15330338.
Gerhard DS; Wagner L; Feingold EA; et al. (2004). „The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)”. Genome Res. 14 (10B): 2121—7. PMC 528928  . PMID 15489334. doi:10.1101/gr.2596504.
Rodd ZA; McKinzie DL; Bell RL; et al. (2006). „The metabotropic glutamate 2/3 receptor agonist LY404039 reduces alcohol-seeking but not alcohol self-administration in alcohol-preferring (P) rats”. Behav. Brain Res. 171 (2): 207—15. PMID 16678921. doi:10.1016/j.bbr.2006.03.032.

Spoljašnje veze

„Metabotropic Glutamate Receptors: mGlu₂”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Архивирано из оригинала 19. 03. 2012. г.

[pmid7620613-1] Flor PJ, Lindauer K, Puttner I, Ruegg D, Lukic S, Knopfel T, Kuhn R (1995). „Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 2”. Eur J Neurosci. 7 (4): 622—9. PMID 7620613. doi:10.1111/j.1460-9568.1995.tb00666.x.

[entrez-2] а ^б „Entrez Gene: GRM2 glutamate receptor, metabotropic 2”.

[3] Fraley ME (2009). „Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia”. Expert Opin Ther Pat. 19 (9): 1259—75. PMID 19552508. doi:10.1517/13543770903045009.

[pmid19079073-4] Conn PJ, Jones CK (2009). „Promise of mGluR2/3 activators in psychiatry”. Neuropsychopharmacology. 34 (1): 248—9. PMC 2907744  . PMID 19079073. doi:10.1038/npp.2008.156.

[5] Dhanya RP; Sidique S; Sheffler DJ; et al. (2011). „Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats”. J. Med. Chem. 54 (1): 342—53. PMC 3071440  . PMID 21155570. doi:10.1021/jm1012165.

[pmid20005096-6] D'Alessandro PL, Corti C, Roth A, Ugolini A, Sava A, Montanari D, Bianchi F, Garland SL, Powney B, Koppe EL, Rocheville M, Osborne G, Perez P, de la Fuente J, De Los Frailes M, Smith PW, Branch C, Nash D, Watson SP (2010). „The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2”. Bioorg. Med. Chem. Lett. 20 (2): 759—62. PMID 20005096. doi:10.1016/j.bmcl.2009.11.032.

[pmid19932615-7] Tresadern G, Cid JM, Macdonald GJ, Vega JA, de Lucas AI, García A, Matesanz E, Linares ML, Oehlrich D, Lavreysen H, Biesmans I, Trabanco AA (2010). „Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor”. Bioorg. Med. Chem. Lett. 20 (1): 175—9. PMID 19932615. doi:10.1016/j.bmcl.2009.11.008.

[8] EJ Brnardic 2010

[9] Zhang L; Rogers BN; Duplantier AJ; et al. (2008). „3-(Imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers: a novel series of mGluR2 positive allosteric modulators”. Bioorganic & Medicinal Chemistry Letters. 18 (20): 5493—6. PMID 18812259. doi:10.1016/j.bmcl.2008.09.026.

[10] Galici R; Jones CK; Hemstapat K; et al. (2006). „Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice”. J. Pharmacol. Exp. Ther. 318 (1): 173—85. PMID 16608916. doi:10.1124/jpet.106.102046.

[11] Bonnefous C; Vernier JM; Hutchinson JH; et al. (2005). „Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor”. Bioorg. Med. Chem. Lett. 15 (19): 4354—8. PMID 16046122. doi:10.1016/j.bmcl.2005.06.062.

[12] Johnson MP; Baez M; Jagdmann GE; et al. (2003). „Discovery of allosteric potentiators for the metabotropic glutamate 2 receptor: synthesis and subtype selectivity of N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2- trifluoroethylsulfonyl)pyrid-3-ylmethylamine”. J. Med. Chem. 46 (15): 3189—92. PMID 12852748. doi:10.1021/jm034015u.

[13] Johnson MP; Barda D; Britton TC; et al. (2005). „Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s)”. Psychopharmacology (Berl.). 179 (1): 271—83. PMID 15717213. doi:10.1007/s00213-004-2099-9.

[14] Schaffhauser H; Rowe BA; Morales S; et al. (2003). „Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2”. Mol. Pharmacol. 64 (4): 798—810. PMID 14500736. doi:10.1124/mol.64.4.798.

[15] Barda DA, Wang ZQ, Britton TC, et al. (2004). „SAR study of a subtype selective allosteric potentiator of metabotropic glutamate 2 receptor, N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide”. Bioorg. Med. Chem. Lett. 14 (12): 3099—102. PMID 15149652. doi:10.1016/j.bmcl.2004.04.017.

[16] Pinkerton AB; Vernier JM; Schaffhauser H; et al. (2004). „Phenyl-tetrazolyl acetophenones: discovery of positive allosteric potentiatiors for the metabotropic glutamate 2 receptor”. J. Med. Chem. 47 (18): 4595—9. PMID 15317469. doi:10.1021/jm040088h.

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