Conserved Protein Domain Family
7tmC_mGluRs_group2_3

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cd15934: 7tmC_mGluRs_group2_3 
metabotropic glutamate receptors in group 2 and 3, member of the class C family of seven-transmembrane G protein-coupled receptors
The metabotropic glutamate receptors (mGluRs) are homodimeric class C G-protein coupled receptors which are activated by glutamate, the major excitatory neurotransmitter of the CNS. The mGluRs are involved in regulating neuronal excitability and synaptic transmission via intracellular activation of second messenger signaling pathways. While the ionotropic glutamate receptor subtypes (AMPA, NMDA, and kainite) mediate fast excitatory postsynaptic transmission, mGluRs are known to mediate slower excitatory postsynaptic responses and to be involved in synaptic plasticity in the mammalian brain. In addition to seven-transmembrane helices, the class C GPCRs are characterized by a large N-terminal extracellular Venus flytrap-like domain, which is composed of two adjacent lobes separated by a cleft which binds an endogenous ligand. Moreover, they exist as either homo- or heterodimers, which are essential for their function. For instance, mGluRs form homodimers via interactions between the N-terminal Venus flytrap domains and the intermolecular disulphide bonds between cysteine residues located in the cysteine-rich domain (CRD). At least eight different subtypes of metabotropic receptors (mGluR1-8) have been identified and further classified into three groups based on their sequence homology, pharmacological properties, and signaling pathways. Group 1 (mGluR1 and mGluR5) receptors are predominantly located postsynaptically on neurons and are involved in long-term synaptic plasticity in the brain, including long-term potentiation (LTP) in the hippocampus and long-term depression (LTD) in the cerebellum. They are coupled to G(q/11) proteins, thereby activating phospholipase C to generate inositol-1,4,5-triphosphate (IP3) and diacyglycerol (DAG), which in turn lead to Ca2+ release and protein kinase C activation, respectively. Group I mGluR expression is shown to be strongly upregulated in animal models of epilepsy, brain injury, inflammatory, and neuropathic pain, as well as in patients with amyotrophic lateral sclerosis or multiple sclerosis. Group 2 (mGluR2 and mGluR3) and 3 (mGluR4, mGluR6, mGluR7, and mGluR8) receptors are predominantly localized presynaptically in the active region of neurotransmitter release. They are coupled to (Gi/o) proteins, which leads to inhibition of adenylate cyclase activity and cAMP formation, and consequently to a decrease in protein kinase A (PKA) activity. Ultimately, activation of these receptors leads to inhibition of neurotransmitter release such as glutamate and GABA via inhibition of Ca2+ channels and activation of K+ channels. Furthermore, while activation of Group 1 mGluRs increases NMDA (N-methyl-D-aspartate) receptor activity and risk of neurotoxicity, Group 2 and 3 mGluRs decrease NMDA receptor activity and prevent neurotoxicity.
Statistics
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PSSM-Id: 320600
View PSSM: cd15934
Aligned: 28 rows
Threshold Bit Score: 422.021
Threshold Setting Gi: 239938639
Created: 11-Jul-2014
Updated: 26-Jul-2017
Structure
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Aligned Rows:
  next features
Feature 1:putative allosteric modulator binding site [chemical binding site]
Evidence:
  • Comment:based on the binding of human mGluR1 receptor to a negative allosteric modulator FITM (contacts at 4A)

Sequence Alignment
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Format: Row Display: Color Bits: Type Selection:
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                  #           ##  ##  #  
gi 12644040   582 PWAVVPVFVAILGIIATTFVIVTFVRYNDtpiVRASGRELSYVLLTGIFLCYSITFLMIaapdTIICSFRRVFLGLGMCF 661
gi 239938639  584 PWAAPPLLLAVLGIVATTTVVATFVRYNNtpiVRASGRELSYVLLTGIFLIYAITFLMVaepgAAVCAARRLFLGLGTTL 663
gi 316975822  561 WWAVVPATFSAVGIAATCFVVYMFIKYNNtpaIKASGRELCYVMLIGIFCSYLITYPMLnppsKITCGILRMGIGLCSCI 640
gi 321476275  577 PWAIVPLVFTALGVTATLFTLTVFLRYNStpmIMASGRELCYLLLTGILLCYLMAIPILakpnVFTCSLLRVGLGFALCL 656
gi 556096503  420 LWFILPVAFSGVGVLCTAAVLVIFIHFNTtpvIMACGRELCYLLLLGIFLSYGTSFVMLakpsVIMCALRRLGLGVSLCF 499
gi 307212713  332 PWALVPLIFASIGILSTLFTTVVFIRFNRtpvIMASGRELCYVLLVGILSCYGMSFVILskptTWNCTYLRIGLGLCLSI 411
gi 443707626  518 AWAIVPVVFAVCGMLTTLFVLLVFVRFDDtpvIMASGRELCYVMVAGLLLSYVMTFIMVakpsLMSCTLLRIGLGLSMCI 597
gi 25149329   612 TWSLIPAAFSTLGIASTIFVVSVFLKFSNtpvIMASGRELCYCMMSGIGMCYTLTFFLVsqptVITCSMTRILMGLSMSA 691
gi 405953198  371 FWMLLPVAFTSIGAVLTILVIAVFIRYNEtpvIMASGRELCYVLLIGILMAYGTSVMMLvrptVILCTLRRLGLGVSLCL 450
gi 291236851  584 AWAIATGAFALTGIIFEVFIIAIFIAYNNtplIRASGRELMFVLLFGIFICYGMTFVIMtkptPTKCCMERLGLGLCLVT 663
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                         
gi 12644040   662 SYAALLTKTNRIhrifeqgkksv-tapkfispasQLVITFSLISVQLLGVFVWFVVDPphiiidygeqrtldpekargvl 740
gi 239938639  664 SYSALLTKTNRIyrifeqgkrsv-tpppfisptsQLVITFSLTSLQVVGMIAWLGARPphsvidyeeqrtvdpeqargvl 742
gi 316975822  641 IYASIFTKTLRLarifnsavqqm-ksirflspmaQIVICLIIVTVYIFTALIWLIAESpdtvilyp-------drmtair 712
gi 321476275  657 CYSSILTKTNRIsrifnrgskagikrpsytspksQIVICCGLASIQLGGSLVWLMFERpstkevhp-------qpltail 729
gi 556096503  500 IYAALLTKTNRIyrifnsgikamvkrpgytspksQILICICLVSVQFIGGLTWLGFEKpdtvqhyd-------qndyivl 572
gi 307212713  412 CYSAILTKTNRIsrifnqgtkri-krlsytspksQVVIASGITAVQLIGTTVWLIIEPpdtteihp-------yplsavl 483
gi 443707626  598 CYSAILTKTNRIsrifnrgvkamvkrpsytsprsQLVICACLVSVQVFGAITWVIMDPpgvthtyp-------drktvvl 670
gi 25149329   692 IYAAIITKTNRLarvfkpdsaq---rprfitpkaQVGICMGIVSVQLIGTFVWILFDPpgtmivfp-------trteavl 761
gi 405953198  451 IYAAMLTKTNRIyrifnngikamvkrpsytsprsQIVICFGIVSVQIVGGITWLGFEKpdtmfvlq-------nqeylvl 523
gi 291236851  664 CYAALLTKTNRIsrifnqgiksa-irpkytspksQIVICVALISLQVLGVTVWLVLDPpqtrveyi-------srdravl 735
                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1            #    #  ##  #                                 #  ##  #   #            ##  #  
gi 12644040   741 kCDISDLSLICSLGYSILLMVTCTVYAIKTRGVpetFNEAKPIGFTMYTTCIIWLAFIPIFFgtaqsaekMYIQTTTLTV 820
gi 239938639  743 kCDMSDLSLIGCLGYSLLLMVTCTVYAIKARGVpetFNEAKPIGFTMYTTCIIWLAFVPIFFgtaqsaekIYIQTTTLTV 822
gi 316975822  713 sCKGATVTFPLSMIYNVLLIILCTVYAFKTRKIpenFNETKYIGFTMYATCIIWLAFIPIYFgtn---qnFKIQTTSLCM 789
gi 321476275  730 tCGVSNLSLVLSLLYNMLLIILCTFYAFKTRKIpenFNEAKYIGFTMYSTCIVWLAFVAIYFgty---ndYKIQTATLCV 806
gi 556096503  573 kCKSSQIATVISLFYNIFIIVLCTVYAFKTRKIpqnFNEAKYIAFTMYSTCIVWLAFIPIYFgan---hdFKIEIISLCM 649
gi 307212713  484 tCRVSTFSLMMSLVYNMFLILMCTLYAFKTRKIpedFNEAKYIGFTMYSTCIVWLAFVPIYFgt-----nNDYKIASMCM 558
gi 443707626  671 rCRSNNVAVVLSLLYNMVLIIMCTVYAFKTRKIpenFNEAKYIAFTMYSTCIVWLAFVPIYFgtk---ndFKIQIMALCM 747
gi 25149329   762 tCKATTSHLLISLLYNILLIVACTVYAFKTRKIpenFNETRHIGFTMYSTCILWLAFGPIYFatq---sdFRIQITSLCM 838
gi 405953198  524 kCRASQTAIIVSLTYNIVLIIICTVYGVKTRKIpqnFNEAKCIAFTMYSTCIVWLAFIPIYFgas--ggdFKIEVTSLCM 601
gi 291236851  736 rCATSDSTLMTSLLYNMLLIVLCTVYAFKTRKIpenFNEAKFIGFTMYTTCIVWLAFLCIYFgts--dkdPKIQMTSLSF 813
                         250       260
                  ....*....|....*....|...
Feature 1         #   #                  
gi 12644040   821 SMSLSASVSLGMLYMPKVYIIIF 843
gi 239938639  823 SLSLSASVSLGMLYVPKTYVILF 845
gi 316975822  790 CISLSGTVALCCFFAPKVYIVLF 812
gi 321476275  807 CVNISASVALGCLFVPKVYIVLF 829
gi 556096503  650 CVSISATVALFCLFAPKVYIVLL 672
gi 307212713  559 CINISASVALGCLFTPKVYLVLF 581
gi 443707626  748 CISISATVQLGCLFVPKVYIVLF 770
gi 25149329   839 CISLSGTVALICFFAPKVYIVLF 861
gi 405953198  602 CVSISATVALVCIFAPKVYIVLL 624
gi 291236851  814 TVSMSASVVLVLLFVPKVYIVVF 836

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