Role of dimer interface in activation and desensitization in AMPA receptors.
The conversion of chemical to electrical signals by the AMPA receptors is the key step by which these proteins control cognitive and motor responses. Here, we have used luminescence resonance energy transfer (LRET) to gain insight into the conformational changes induced by glutamate binding in the agonist-binding domain in functional AMPA receptors expressed in oocytes and HEK-293 cells. The LRET-based distances indicate that the interface between the upper lobes of the agonist-binding domain within a dimer is in a decoupled state in the unligated Apo state of the receptor. Agonist binding results in the formation of the dimer interface in the open-channel form of the receptor. In the continued presence of glutamate when the receptor is primarily in the desensitized state, the dimer interface is decoupled, confirming that the decoupling of the dimer interface leads to channel closure. The LRET distances also indicate that the dimer interface is preformed before activation in the L484Y mutation and also is formed in the antagonist (ZK200775)-bound form of the AMPA receptor. These results suggests that, although the preformation of the interface is not sufficient to drive channel activation, it could play a role in the energetics of activation and hence modulation of the receptor by auxiliary proteins or small molecules.
Gonzalez
Jennifer
J
Center for Membrane Biology, Department of Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, TX 77030, USA.
Du
Mei
M
Parameshwaran
Kodeeswaran
K
Suppiramaniam
Vishnu
V
Jayaraman
Vasanthi
V
D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D018091:Receptors, AMPA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
D018091:Receptors, AMPA
J Neurosci. 2009 Sep 23;29(38):11912-23
19776277
Cell. 2006 Oct 6;127(1):85-97
17018279
J Biol Chem. 2005 Mar 11;280(10):8633-6
15632199
Biochemistry. 2002 Dec 31;41(52):15635-43
12501192
Neuron. 2000 Oct;28(1):165-81
11086992
Biochemistry. 2002 Aug 20;41(33):10472-81
12173934
Nature. 2002 May 16;417(6886):245-53
12015593
Nature. 1998 Oct 29;395(6705):913-7
9804426
J Am Chem Soc. 2001 Jul 25;123(29):7067-73
11459485
Nat Neurosci. 2003 Aug;6(8):803-10
12872125
Nature. 1999 Dec 16;402(6763):809-13
10617201
Nature. 2006 Mar 23;440(7083):456-62
16554805
Annu Rev Neurosci. 1994;17:31-108
8210177
Curr Opin Neurobiol. 2005 Jun;15(3):282-8
15919192
Biochemistry. 2008 Sep 23;47(38):10027-32
18759455
Annu Rev Biophys Biomol Struct. 1994;23:319-48
7919785
Nature. 2009 Dec 10;462(7274):745-56
19946266
Curr Drug Targets. 2007 May;8(5):573-82
17504102
Biochemistry. 2008 Dec 30;47(52):13831-41
19102704
EMBO J. 2009 Jun 17;28(12):1812-23
19461580
J Physiol. 2004 Jan 15;554(Pt 2):249-53
14645452
J Mol Biol. 2002 Sep 6;322(1):93-109
12215417
Biochemistry. 1978 Nov 14;17(23):5064-70
718874
Nat Rev Neurosci. 2002 Feb;3(2):91-101
11836517