Binding of amyloid beta peptide to beta2 adrenergic receptor induces PKA-dependent AMPA receptor hyperactivity.
Progressive decrease in neuronal function is an established feature of Alzheimer's disease (AD). Previous studies have shown that amyloid beta (Abeta) peptide induces acute increase in spontaneous synaptic activity accompanied by neurotoxicity, and Abeta induces excitotoxic neuronal death by increasing calcium influx mediated by hyperactive alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. An in vivo study has revealed subpopulations of hyperactive neurons near Abeta plaques in mutant amyloid precursor protein (APP)-transgenic animal model of Alzheimer's disease (AD) that can be normalized by an AMPA receptor antagonist. In the present study, we aim to determine whether soluble Abeta acutely induces hyperactivity of AMPA receptors by a mechanism involving beta(2) adrenergic receptor (beta(2)AR). We found that the soluble Abeta binds to beta(2)AR, and the extracellular N terminus of beta(2)AR is critical for the binding. The binding is required to induce G-protein/cAMP/protein kinase A (PKA) signaling, which controls PKA-dependent phosphorylation of GluR1 and beta(2)AR, and AMPA receptor-mediated excitatory postsynaptic currents (EPSCs). beta(2)AR and GluR1 also form a complex comprising postsynaptic density protein 95 (PSD95), PKA and its anchor AKAP150, and protein phosphotase 2A (PP2A). Both the third intracellular (i3) loop and C terminus of beta(2)AR are required for the beta(2)AR/AMPA receptor complex. Abeta acutely induces PKA phosphorylation of GluR1 in the complex without affecting the association between two receptors. The present study reveals that non-neurotransmitter Abeta has a binding capacity to beta(2)AR and induces PKA-dependent hyperactivity in AMPA receptors.
Wang
Dayong
D
Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, 407 S. Goodwin Ave., Urbana, IL 61801, USA.
Govindaiah
G
G
Liu
Ruijie
R
De Arcangelis
Vania
V
Cox
Charles L
CL
Xiang
Yang K
YK
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D018091:Receptors, AMPA; D018343:Receptors, Adrenergic, beta-2; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054648:Protein Phosphatase 2
Curr Opin Cell Biol. 2007 Apr;19(2):192-8
17317140
J Biol Chem. 2001 May 18;276(20):17301-6
11278679
Chem Rev. 2001 Aug;101(8):2243-70
11749372
J Biol Chem. 2008 Jan 25;283(4):1799-807
18056263
Nature. 2006 Mar 16;440(7082):352-7
16541076
Nat Rev Drug Discov. 2002 Mar;1(3):187-97
12120503
Epilepsia. 2006 May;47(5):867-72
16686651
Annu Rev Neurosci. 2004;27:107-44
15217328
Tijdschr Gerontol Geriatr. 2001 Feb;32(1):17-23
11293840
Neuron. 2006 Dec 7;52(5):831-43
17145504
Neuroscience. 2005;135(4):1193-202
16181736
Curr Mol Pharmacol. 2009 Jan;2(1):77-82
20021448
Neurosci Lett. 2004 Aug 19;366(3):320-5
15288443
J Biol Chem. 2009 Nov 20;284(47):32279-87
19706594
J Neurosci. 2000 Jan 1;20(1):89-102
10627585
EMBO J. 2003 Dec 15;22(24):6419-29
14657015
Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5161-6
16549764
J Biol Chem. 2009 Mar 6;284(10):6554-65
19074441
J Neurosci. 2001 Jan 1;21(1):RC120
11150356
Am J Geriatr Psychiatry. 2008 Nov;16(11):883-92
18978249
J Biol Chem. 2004 Jan 2;279(1):686-91
14559905
Nat Neurosci. 2008 Mar;11(3):301-8
18297066
Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):909-14
15644445
Nature. 2005 Sep 22;437(7058):569-73
16177793
Nat Neurosci. 2009 Dec;12(12):1567-76
19935655
Science. 2008 Sep 19;321(5896):1686-9
18802001
Science. 2002 Jul 19;297(5580):353-6
12130773
Neuroscience. 2006 Oct 27;142(3):655-60
16904834
Dement Geriatr Cogn Disord. 2007;24(5):369-74
17914261
J Neurosci. 2006 Dec 27;26(52):13443-53
17192427
Nat Med. 2008 Aug;14(8):837-42
18568035
J Biol Chem. 2008 Jul 4;283(27):19066-76
18463098
Nature. 2002 Apr 4;416(6880):535-9
11932745
Mol Pharmacol. 2007 Aug;72(2):429-39
17510209
J Neurosci. 1999 Oct 15;19(20):8876-84
10516307
Neuropsychopharmacology. 2007 Jun;32(6):1261-71
17133263
Neuron. 2003 Mar 27;37(6):925-37
12670422
Endocr Rev. 2000 Feb;21(1):90-113
10696571
J Neurosci. 2002 Apr 15;22(8):3044-51
11943807
Science. 2001 Jul 6;293(5527):98-101
11441182
J Neurosci. 2007 Mar 14;27(11):2866-75
17360908
J Neurol Sci. 1987 Apr;78(2):151-64
3572454
Exp Neurol. 2008 Mar;210(1):7-13
18053990
Neurosci Lett. 2001 Apr 20;302(2-3):97-100
11290396
EMBO J. 2010 Jan 20;29(2):482-95
19942860
Ann Neurol. 1999 Jan;45(1):82-91
9894881
J Neurosci. 2008 Jan 23;28(4):788-97
18216187
J Neurochem. 2003 Apr;85(2):443-53
12675920
Cell. 2007 Oct 5;131(1):160-73
17923095
Brain Res. 2008 May 19;1210:216-22
18423577
Pharmacol Biochem Behav. 2007 Jun-Jul;87(2):241-9
17537494
Neuron. 2008 Jul 31;59(2):214-25
18667150
Proc Natl Acad Sci U S A. 2004 Oct 5;101(40):14326-32
15388848
Fortschr Neurol Psychiatr. 2007 Apr;75(4):199-210
17200914
Neuron. 2000 Jul;27(1):107-19
10939335
Nature. 2005 Jul 28;436(7050):554-8
16049488
J Neurosci. 1997 Jul 15;17(14):5573-80
9204938
Proc Natl Acad Sci U S A. 2007 May 1;104(18):7682-7
17452637
Neurosci Lett. 2001 Mar 23;301(1):59-63
11239716
Nat Med. 2006 Dec;12(12):1390-6
17115048