| Structural highlights
Disease
CCG2_MOUSE Note=Defects in Cacng2 cause the stargazer (stg) phenotype. Stg mice have spike-wave seizures characteristic of absence epilepsy, with accompanying defects in the cerebellum and inner ear.
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_MOUSE 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 (By similarity).
Publication Abstract from PubMed
AMPA receptors (AMPARs) mediate fast excitatory neurotransmission. Gating of AMPARs starts with agonist binding and transition into a non-conducting pre-active state, followed by transition into conducting open or non-conducting desensitized states. While the terminal apo, open and desensitized states have been structurally characterized, the intermediate pre-active state has remained an enigma. Compared to full agonist glutamate, partial agonists reduce the maximal occupancy of the open state and increase the probability of the pre-active state occurrence. Here we use different partial agonists and time-resolved cryo-electron microscopy (cryo-EM) to capture a structural ensemble of GluA2-gamma2 AMPAR complexes in the closed apo, pre-active, open and desensitized states. Binding of partial agonists to the ligand-binding domain (LBD) results in different extents of LBD clamshell closure, with closures exceeding a threshold of ~17 degrees resulting in the open and desensitized states and smaller closures stabilizing the pre-active state. The pre-active state has a distinct gate conformation intermediate between the other two discrete states, completely open and closed. Combined with single-channel current recordings and molecular dynamics simulations, our structural results reveal the complete gating pathway of AMPARs and shed light on the molecular mechanisms of partial agonism and pre-activation.
Pre-activation and gating pathway of AMPA receptors revealed by full and partial agonists.,Newton TP, Aktolun M, Yelshanskaya MV, Alekseev AA, Yen LY, Gangwar SP, Sobolevsky IA, Kurnikova MG, Sobolevsky AI Nat Struct Mol Biol. 2026 Sep 9. doi: 10.1038/s41594-026-01882-9. PMID:42717062[15]
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
- ↑ Sun Y, Olson R, Horning M, Armstrong N, Mayer M, Gouaux E. Mechanism of glutamate receptor desensitization. Nature. 2002 May 16;417(6886):245-53. PMID:12015593 doi:10.1038/417245a
- ↑ Jin R, Banke TG, Mayer ML, Traynelis SF, Gouaux E. Structural basis for partial agonist action at ionotropic glutamate receptors. Nat Neurosci. 2003 Aug;6(8):803-10. PMID:12872125 doi:10.1038/nn1091
- ↑ Armstrong N, Mayer M, Gouaux E. Tuning activation of the AMPA-sensitive GluR2 ion channel by genetic adjustment of agonist-induced conformational changes. Proc Natl Acad Sci U S A. 2003 May 13;100(10):5736-41. Epub 2003 May 2. PMID:12730367 doi:https://dx.doi.org/10.1073/pnas.1037393100
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- ↑ Frandsen A, Pickering DS, Vestergaard B, Kasper C, Nielsen BB, Greenwood JR, Campiani G, Fattorusso C, Gajhede M, Schousboe A, Kastrup JS. Tyr702 is an important determinant of agonist binding and domain closure of the ligand-binding core of GluR2. Mol Pharmacol. 2005 Mar;67(3):703-13. Epub 2004 Dec 9. PMID:15591246 doi:10.1124/mol.104.002931
- ↑ Armstrong N, Jasti J, Beich-Frandsen M, Gouaux E. Measurement of conformational changes accompanying desensitization in an ionotropic glutamate receptor. Cell. 2006 Oct 6;127(1):85-97. PMID:17018279 doi:10.1016/j.cell.2006.08.037
- ↑ Kasper C, Pickering DS, Mirza O, Olsen L, Kristensen AS, Greenwood JR, Liljefors T, Schousboe A, Watjen F, Gajhede M, Sigurskjold BW, Kastrup JS. The structure of a mixed GluR2 ligand-binding core dimer in complex with (S)-glutamate and the antagonist (S)-NS1209. J Mol Biol. 2006 Apr 7;357(4):1184-201. Epub 2006 Jan 31. PMID:16483599 doi:10.1016/j.jmb.2006.01.024
- ↑ 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
- ↑ Ahmed AH, Wang S, Chuang HH, Oswald RE. Mechanism of AMPA receptor activation by partial agonists: disulfide trapping of closed lobe conformations. J Biol Chem. 2011 Aug 16. PMID:21846932 doi:10.1074/jbc.M111.269001
- ↑ Newton TP, Aktolun M, Yelshanskaya MV, Alekseev AA, Yen LY, Gangwar SP, Sobolevsky IA, Kurnikova MG, Sobolevsky AI. Pre-activation and gating pathway of AMPA receptors revealed by full and partial agonists. Nat Struct Mol Biol. 2026 Sep 9. doi: 10.1038/s41594-026-01882-9. PMID:42717062 doi:https://dx.doi.org/10.1038/s41594-026-01882-9
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