Conserved Protein Domain Family
7tmC_mGluR2

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cd15447: 7tmC_mGluR2 
metabotropic glutamate receptor 2 in group 2, member of the class C family oof 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: 320563
View PSSM: cd15447
Aligned: 4 rows
Threshold Bit Score: 494.833
Threshold Setting Gi: 158705915
Created: 2-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 158705915 566 AWAVGPVTIACLGALATLFVLGVFVRHNAtpvVKASGRELCYILLGGVFLCYCMTFIFIakpsTAVCTLRRLGLGTAFSV 645
gi 82257936  539 AWAIGPVTISCLGILCTLSVVGLFFKYNEtpvVKASGRELSYILLLGVLMCYLMTFIYIakpsTAICTLRRLGLGTSFAV 618
gi 513204739 579 VWAIGPVTISCLGFISTLFVFGVFMKNNDtpiVKASGRELCYILLTGVLMCYSMTFIFIakpsTEVCTLRRLGLGTSFAV 658
gi 512838360 562 AWAVGPVCLSCLGLLSTLFVIGVFVQNNNtpiVKASGRELCYILLCGVLLCYAMTFIFIskpsTSVCTLRRLGLGTSFAI 641
                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                     #  
gi 158705915 646 CYSALLTKTNRIARIFggaregaqrprfisPASQVAICLALISGQLLIVAAWLVVEAPgigketaperrevvtlrCNHRD 725
gi 82257936  619 CYSALLTKTNRIARIFsgvkdgaqrprfisPASQVAICGALISCQLLVALIWLMVEGPgvrkevnserrnvvilkCNSRD 698
gi 513204739 659 CYSALLTKTNRIARIFsgvkegvqrprfisPTSQVVICMALISCQLIIVIIWLLVEAPgtgketepdkryivtlkCNNRD 738
gi 512838360 642 CYSALLTKTNRIARIFsgardgvqrprfisPASQVGICLVLISCQLLVVLIWLLFEPPgtrkdtapdkryivtlkCNSGD 721
                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1          #  ##  #                                 #  ##  #   #         ##  #  #   #    
gi 158705915 726 ASMLGSLAYNVLLIALCTLYAFKTRKCpenFNEAKFIGFTMYTTCIIWLAFLPIFYvtssdYRVQTTTMCVSVSLSGSVV 805
gi 82257936  699 SSMLVSLTYNCVLIILCTVYAFKTRKCpenFNEAKFIGFTMYTTCIIWLAFQPIFYvtasdYRVQTTTMCISVSLSGSVV 778
gi 513204739 739 SNMLISLTYNVLLIVLCTVYAFKTRKCpenFNEAKFIGFTMYTTCIIWLAFLPIFYvtssdYRVQTTTMCISVSLSGTVV 818
gi 512838360 722 GSMLISLSYNVLLVLLCTLYAFKTRKCpenFNEAKFIGFTMYTTCIIWLAFLPIYYvtssdYRVQTTTLCVSVSLSGSVV 801
                        250
                 ....*....|....
Feature 1                      
gi 158705915 806 LGCLFAPKLHIILF 819
gi 82257936  779 LGCLFAPKVHIILF 792
gi 513204739 819 LGCLFTPKLHIILF 832
gi 512838360 802 LGCLFTPKLHIIIF 815

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