Conserved Protein Domain Family
7tmC_mGluR4

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cd15452: 7tmC_mGluR4 
metabotropic glutamate receptor 4 in group 3, member of the class C family of seven-transmembrane G protein-coupled receptors
The receptors in group 3 include mGluRs 4, 6, 7, and 8. 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: 320568
View PSSM: cd15452
Aligned: 4 rows
Threshold Bit Score: 666.683
Threshold Setting Gi: 301620299
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 545273585 585 PWAVIPVLIAILGIIATLFVVVTFIRYNDtpiVKASGRELSYVLLTGIFLCYATTFLMIstpdVGICSLRRIFLGLGMSI 664
gi 2495077   586 PWAVLPLFLAVVGIAATLFVVITFVRYNDtpiVKASGRELSYVLLAGIFLCYATTFLMIaepdLGTCSLRRIFLGLGMSI 665
gi 363743217 586 PWAVVPVFIAIVGIIATLFVVVTFVRYNDtpiVKASGRELSYVLLTGIFLCYATTFLMIaepdLSTCSLRRIFLGLGMSI 665
gi 301620299 588 PWAVVPLLLAVLGIIATLVVVGTFMRYNDtpiVKASGRELSYVLLSGIFLCYVNTFIMVaqpgFGTCSLRRVFLGLGMSI 667
                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                        
gi 545273585 665 SYAALLTKTNRIYRILEQGKmtvsaPRFISPASQLIITFSLISVQLLGVCIWFAVDPsqaliDYEDQRTIDPEMARGVLK 744
gi 2495077   666 SYAALLTKTNRIYRIFEQGKrsvsaPRFISPASQLAITFSLISLQLLGICVWFVVDPshsvvDFQDQRTLDPRFARGVLK 745
gi 363743217 666 SYAALLTKTNRIYRIFEQGKksvsaPRFISPASQLVITFSLISLQLVGVCIWFIVDPshsviDYEDQRTTNPHFARGILK 745
gi 301620299 668 SYAALLTKTNRIYRIFEQGKrsvsaPRYISPSSQLVITASLSSIQLLGVLVWFLVDPsrpivDYENQRTPDPQLTRGVLK 747
                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1          #    #  ##  #                                 #  ##  #   #            ##  #  #
gi 545273585 745 CDISDLSLICLLGYSMLLMVTCTVYAIKTRGVPEtFNEAKPIGFTMYTTCIIWLAFIPIFFGTSQstEKMYIQTTTLTIS 824
gi 2495077   746 CDISDLSLICLLGYSMLLMVTCTVYAIKTRGVPEtFNEAKPIGFTMYTTCIVWLAFIPIFFGTSQsaDKLYIQTTTLTVS 825
gi 363743217 746 CDISDLSLICLLGYSMLLMVTCTVYAIKTRGVPEtFNEAKPIGFTMYTTCIVWLAFIPIFFGTSQsaEKMYIQTTTLTIS 825
gi 301620299 748 CDISDLSLICLLGYSMLLMVTCTVYAIKTRGVPEtFNEAKPIGFTMYTTCIIWLAFIPIFFGTAQsaEKMHIQTTTLTIS 827
                        250       260       270       280       290       300       310       320
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1           #                                                                            
gi 545273585 825 VSLSASVSLGMLYMPKVYVVLFHPEQNVAKRstRSLKAVVTAATMSNKFNPKASLRPNGEAKSELCENLETQGLSPKQTY 904
gi 2495077   826 VSLSASVSLGMLYMPKVYIILFHPEQNVPKRk-RSLKAVVTAATMSNKFTQKGNFRPNGEAKSELCENLEAPALATKQTY 904
gi 363743217 826 VSLSASVSLGMLYMPKVYIILFHPEQNVPKRk-RSLKAVVTAATMSNKFSQKGGFRPNGEAKSELCENLETQALSTKQTY 904
gi 301620299 828 VSLSASVSLGMLYMPKVYVILFHPEQNVPKRk-RSLKAVVTAATMSNKFTQKGSYRPNGEAKTELCDNMEVQALATKPTY 906

                 ....*...
Feature 1                
gi 545273585 905 ISYSNHAI 912
gi 2495077   905 VTYTNHAI 912
gi 363743217 905 VSYSNHAI 912
gi 301620299 907 VSYSNHAI 914

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