| Structural highlights
Function
[GRIA2_RAT] Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [CCG2_RAT] Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization. Does not show subunit-specific AMPA receptor regulation and regulates all AMPAR subunits. Thought to stabilize the calcium channel in an inactivated (closed) state.[15] [16] [17] [18] [19]
Publication Abstract from PubMed
AMPA receptors mediate fast excitatory neurotransmission in the mammalian brain and transduce the binding of presynaptically released glutamate to the opening of a transmembrane cation channel. Within the postsynaptic density, however, AMPA receptors coassemble with transmembrane AMPA receptor regulatory proteins (TARPs), yielding a receptor complex with altered gating kinetics, pharmacology, and pore properties. Here, we elucidate structures of the GluA2-TARP gamma2 complex in the presence of the partial agonist kainate or the full agonist quisqualate together with a positive allosteric modulator or with quisqualate alone. We show how TARPs sculpt the ligand-binding domain gating ring, enhancing kainate potency and diminishing the ensemble of desensitized states. TARPs encircle the receptor ion channel, stabilizing M2 helices and pore loops, illustrating how TARPs alter receptor pore properties. Structural and computational analysis suggests the full agonist and modulator complex harbors an ion-permeable channel gate, providing the first view of an activated AMPA receptor.
Activation and Desensitization Mechanism of AMPA Receptor-TARP Complex by Cryo-EM.,Chen S, Zhao Y, Wang Y, Shekhar M, Tajkhorshid E, Gouaux E Cell. 2017 Sep 7;170(6):1234-1246.e14. doi: 10.1016/j.cell.2017.07.045. Epub 2017, Aug 17. PMID:28823560[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Jin R, Horning M, Mayer ML, Gouaux E. Mechanism of activation and selectivity in a ligand-gated ion channel: structural and functional studies of GluR2 and quisqualate. Biochemistry. 2002 Dec 31;41(52):15635-43. PMID:12501192
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- ↑ Sobolevsky AI, Rosconi MP, Gouaux E. X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature. 2009 Dec 10;462(7274):745-56. Epub . PMID:19946266 doi:10.1038/nature08624
- ↑ Rossmann M, Sukumaran M, Penn AC, Veprintsev DB, Babu MM, Greger IH. Subunit-selective N-terminal domain associations organize the formation of AMPA receptor heteromers. EMBO J. 2011 Mar 2;30(5):959-71. Epub 2011 Feb 11. PMID:21317873 doi:10.1038/emboj.2011.16
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- ↑ Milstein AD, Zhou W, Karimzadegan S, Bredt DS, Nicoll RA. TARP subtypes differentially and dose-dependently control synaptic AMPA receptor gating. Neuron. 2007 Sep 20;55(6):905-18. PMID:17880894 doi:https://dx.doi.org/10.1016/j.neuron.2007.08.022
- ↑ Kato AS, Siuda ER, Nisenbaum ES, Bredt DS. AMPA receptor subunit-specific regulation by a distinct family of type II TARPs. Neuron. 2008 Sep 25;59(6):986-96. doi: 10.1016/j.neuron.2008.07.034. PMID:18817736 doi:https://dx.doi.org/10.1016/j.neuron.2008.07.034
- ↑ Soto D, Coombs ID, Renzi M, Zonouzi M, Farrant M, Cull-Candy SG. Selective regulation of long-form calcium-permeable AMPA receptors by an atypical TARP, gamma-5. Nat Neurosci. 2009 Mar;12(3):277-85. doi: 10.1038/nn.2266. Epub 2009 Feb 22. PMID:19234459 doi:https://dx.doi.org/10.1038/nn.2266
- ↑ Schwenk J, Harmel N, Zolles G, Bildl W, Kulik A, Heimrich B, Chisaka O, Jonas P, Schulte U, Fakler B, Klocker N. Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors. Science. 2009 Mar 6;323(5919):1313-9. doi: 10.1126/science.1167852. PMID:19265014 doi:10.1126/science.1167852
- ↑ Shi Y, Suh YH, Milstein AD, Isozaki K, Schmid SM, Roche KW, Nicoll RA. Functional comparison of the effects of TARPs and cornichons on AMPA receptor trafficking and gating. Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16315-9. doi:, 10.1073/pnas.1011706107. Epub 2010 Aug 30. PMID:20805473 doi:https://dx.doi.org/10.1073/pnas.1011706107
- ↑ Chen S, Zhao Y, Wang Y, Shekhar M, Tajkhorshid E, Gouaux E. Activation and Desensitization Mechanism of AMPA Receptor-TARP Complex by Cryo-EM. Cell. 2017 Sep 7;170(6):1234-1246.e14. doi: 10.1016/j.cell.2017.07.045. Epub 2017, Aug 17. PMID:28823560 doi:https://dx.doi.org/10.1016/j.cell.2017.07.045
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