Conserved Protein Domain Family
7tmC_mGluR_group2

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cd15284: 7tmC_mGluR_group2 
metabotropic glutamate receptors in group 2, member of the class C family of seven-transmembrane G protein-coupled receptors
The metabotropic glutamate receptors (mGluRs) in group 2 include mGluR 2 and 3. They are homodimeric class C G-protein coupled receptors which are activated by glutamate, the major excitatory neurotransmitter of the CNS. 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 1 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 G(i/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: 320411
View PSSM: cd15284
Aligned: 9 rows
Threshold Bit Score: 475.492
Threshold Setting Gi: 512838360
Created: 7-Feb-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 30913124  575 AWAIGPVTIACLGFMCTCIVITVFIKHNNtplVKASGRELCYILLFGVSLSYCMTFFFIakpsPVICALRRLGLGTSFAI 654
gi 158705915 566 AWAVGPVTIACLGALATLFVLGVFVRHNAtpvVKASGRELCYILLGGVFLCYCMTFIFIakpsTAVCTLRRLGLGTAFSV 645
gi 82257936  539 AWAIGPVTISCLGILCTLSVVGLFFKYNEtpvVKASGRELSYILLLGVLMCYLMTFIYIakpsTAICTLRRLGLGTSFAV 618
gi 513204739 579 VWAIGPVTISCLGFISTLFVFGVFMKNNDtpiVKASGRELCYILLTGVLMCYSMTFIFIakpsTEVCTLRRLGLGTSFAV 658
gi 512838360 562 AWAVGPVCLSCLGLLSTLFVIGVFVQNNNtpiVKASGRELCYILLCGVLLCYAMTFIFIskpsTSVCTLRRLGLGTSFAI 641
gi 449273915 585 AWAIGPVTIACLGFICTFMVIAVFIKHNNtplVKASGRELCYILLFGVFLSYSMTFFFIakpsPAICTLRRLGLGSSFAV 664
gi 76803803  575 AWAIGPVTIACLGFMCTCMVVTVFIKHNNtplVKASGRELCYILLFGVGLSYCMTFFFIakpsPVICALRRLGLGSSFAI 654
gi 545273582 577 AWAIGPISIACVGFICTLMVFIVFIRHNDtplVKASGRELCYILLLGVFMSYVMTFIFIakpsPIVCTLRRLGLGTSFAV 656
gi 512831997 421 AWAIGPVTIACLGFVCTCLVGGVFIKNNStplVKASGRELCYILLIGVFMCYCMTFFFIakpsPVICTLRRLGLGTSFVV 500
                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                      # 
gi 30913124  655 CYSALLTKTNCIARIFdgvknga-qrpkfisPSSQVFICLGLILVQIVMVSVWLILETPgtrrytlpekretvilkCNVK 733
gi 158705915 646 CYSALLTKTNRIARIFggarega-qrprfisPASQVAICLALISGQLLIVAAWLVVEAPgigketaperrevvtlrCNHR 724
gi 82257936  619 CYSALLTKTNRIARIFsgvkdga-qrprfisPASQVAICGALISCQLLVALIWLMVEGPgvrkevnserrnvvilkCNSR 697
gi 513204739 659 CYSALLTKTNRIARIFsgvkegv-qrprfisPTSQVVICMALISCQLIIVIIWLLVEAPgtgketepdkryivtlkCNNR 737
gi 512838360 642 CYSALLTKTNRIARIFsgardgv-qrprfisPASQVGICLVLISCQLLVVLIWLLFEPPgtrkdtapdkryivtlkCNSG 720
gi 449273915 665 CYSALLTKTNCIARIFdgvknga-qrpkfisPSSQVFICLSLILVQIVVVSVWLILEAPgtrrytlpekretvilkCNVK 743
gi 76803803  655 CYSALLTKTNCIARIFdgvknga-qrpkfisPSSQVFICLGLILVQIVMVSVWLILEAPgtrrytlaekretvilkCNVK 733
gi 545273582 657 CYSALLTKTNRIARIFsgvkeggaqrprfisPSSQVFICLSLISVQLLLVSVWLLVEVPgtrrfttpekrqtvilkCNVR 736
gi 512831997 501 CYSALLTKTNRIARIFsgvkdga-qrpkfisPKSQVVICLSLISVQIVVVSVWLMLEFPgtrrytlpekretvilkCNVK 579
                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1           #  ##  #                                 #  ##  #   #         ##  #  #   #   
gi 30913124  734 DSSMLISLTYDVVLVILCTVYAFKTRKCpenFNEAKFIGFTMYTTCIIWLAFLPIFYvtssdYRVQTTTMCISVSLSGFV 813
gi 158705915 725 DASMLGSLAYNVLLIALCTLYAFKTRKCpenFNEAKFIGFTMYTTCIIWLAFLPIFYvtssdYRVQTTTMCVSVSLSGSV 804
gi 82257936  698 DSSMLVSLTYNCVLIILCTVYAFKTRKCpenFNEAKFIGFTMYTTCIIWLAFQPIFYvtasdYRVQTTTMCISVSLSGSV 777
gi 513204739 738 DSNMLISLTYNVLLIVLCTVYAFKTRKCpenFNEAKFIGFTMYTTCIIWLAFLPIFYvtssdYRVQTTTMCISVSLSGTV 817
gi 512838360 721 DGSMLISLSYNVLLVLLCTLYAFKTRKCpenFNEAKFIGFTMYTTCIIWLAFLPIYYvtssdYRVQTTTLCVSVSLSGSV 800
gi 449273915 744 DSSMLISLTYDVILVVLCTVYAFKTRKCpenFNEAKFIGFTMYTTCIIWLAFLPIFYvtssdYRVQTTTMCISVSLSGFV 823
gi 76803803  734 DSSMLISLTYDVILVILCTVYAFKTRKCpenFNEAKFIGFTMYTTCIIWLAFLPIFYvtssdYRVQTTTMCISVSLSGFV 813
gi 545273582 737 DSSMLMSLSYDVVLVVLCTVYAFKTRKCpenFNEAKFIGFTMYTTCIIWLAFLPIFYvtssdYRVQTTTMCISVSLSGFV 816
gi 512831997 580 DSSMLISLTYDVVLVILCTVYAFKTRKCpenFNEAKFIGFTMYTTCIIWLAFLPIFYvtssdYRVQTTTMCISVSLSGFV 659
                        250
                 ....*....|....*
Feature 1                       
gi 30913124  814 VLGCLFAPKVHIVLF 828
gi 158705915 805 VLGCLFAPKLHIILF 819
gi 82257936  778 VLGCLFAPKVHIILF 792
gi 513204739 818 VLGCLFTPKLHIILF 832
gi 512838360 801 VLGCLFTPKLHIIIF 815
gi 449273915 824 VLGCLFAPKVHIILF 838
gi 76803803  814 VLGCLFAPKVHIILF 828
gi 545273582 817 VLGCMFAPKVHIIMF 831
gi 512831997 660 VLGCLFAPKVHIILF 674

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