Home LiteratureArticle Details
PMID: 21172614 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Homeostatic scaling requires group I mGluR activation mediated by Homer1a.

Neuron ·Vol. 68 ·No. 6 ·2010-12-22 ·Pages 1128-42

Hu JH, Park JM, Park S, Xiao B, Dehoff MH, Kim S, Hayashi T, Schwarz MK, Huganir RL, Seeburg PH, Linden DJ, Worley PF

Abstract

Homeostatic scaling is a non-Hebbian form of neural plasticity that maintains neuronal excitability and informational content of synaptic arrays in the face of changes of network activity. Here, we demonstrate that homeostatic scaling is dependent on group I metabotropic glutamate receptor activation that is mediated by the immediate early gene Homer1a. Homer1a is transiently upregulated during increases in network activity and evokes agonist-independent signaling of group I mGluRs that scales down the expression of synaptic AMPA receptors. Homer1a effects are dynamic and play a role in the induction of scaling. Similar to mGluR-LTD, Homer1a-dependent scaling involves a reduction of tyrosine phosphorylation of GluA2 (GluR2), but is distinct in that it exploits a unique signaling property of group I mGluR to confer cell-wide, agonist-independent activation of the receptor. These studies reveal an elegant interplay of mechanisms that underlie Hebbian and non-Hebbian plasticity.

MeSH Terms
Animals Carrier Proteins/genetics,physiology Cells, Cultured Cerebral Cortex/metabolism Excitatory Postsynaptic Potentials/genetics,physiology Homeostasis/genetics,physiology Homer Scaffolding Proteins Mice Mice, Inbred C57BL Mice, Knockout Neuronal Plasticity/genetics,physiology Receptors, Metabotropic Glutamate/metabolism Signal Transduction/genetics,physiology
Chemicals
Carrier Proteins Homer Scaffolding Proteins Receptors, Metabotropic Glutamate metabotropic glutamate receptor type 1
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Hu Jia-Hua
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Park Joo Min
Park Sungjin
Xiao Bo
Dehoff Marlin H
Kim Sangmok
Hayashi Takashi
Schwarz Martin K
Huganir Richard L
Seeburg Peter H
Linden David J
Worley Paul F
References (43)
43 references, click to expand
  1. LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors.
    Neuropharmacology. 1998;37(1):1-12 PMID: 9680254
  2. Altered synaptic plasticity in a mouse model of fragile X mental retardation.
    Proc Natl Acad Sci U S A. 2002 May 28;99(11):7746-50 PMID: 12032354
  3. The self-tuning neuron: synaptic scaling of excitatory synapses.
    Cell. 2008 Oct 31;135(3):422-35 PMID: 18984155
  4. Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites.
    Neuron. 1995 Feb;14(2):433-45 PMID: 7857651
  5. Synapse-associated protein-97 isoform-specific regulation of surface AMPA receptors and synaptic function in cultured neurons.
    J Neurosci. 2003 Jun 1;23(11):4567-76 PMID: 12805297
  6. Attenuation of behavioral effects of cocaine by the Metabotropic Glutamate Receptor 5 Antagonist 2-Methyl-6-(phenylethynyl)-pyridine in squirrel monkeys: comparison with dizocilpine.
    J Pharmacol Exp Ther. 2005 Mar;312(3):1232-40 PMID: 15550570
  7. Tyrosine phosphorylation of GluR2 is required for insulin-stimulated AMPA receptor endocytosis and LTD.
    EMBO J. 2004 Mar 10;23(5):1040-50 PMID: 14976558
  8. Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors.
    Neuron. 1998 Oct;21(4):717-26 PMID: 9808459
  9. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD.
    Neuron. 2008 Jul 10;59(1):70-83 PMID: 18614030
  10. Regulation of metabotropic glutamate receptor signaling, desensitization and endocytosis.
    Pharmacol Ther. 2006 Jul;111(1):260-71 PMID: 16574233
  11. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors.
    Neuron. 2001 Aug 16;31(3):463-75 PMID: 11516402
  12. Spike timing-dependent plasticity of neural circuits.
    Neuron. 2004 Sep 30;44(1):23-30 PMID: 15450157
  13. Sindbis virus: an efficient, broad host range vector for gene expression in animal cells.
    Science. 1989 Mar 3;243(4895):1188-91 PMID: 2922607
  14. Hebb and homeostasis in neuronal plasticity.
    Curr Opin Neurobiol. 2000 Jun;10(3):358-64 PMID: 10851171
  15. AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis.
    Neuron. 2009 Nov 12;64(3):381-90 PMID: 19914186
  16. Alteration of neuronal firing properties after in vivo experience in a FosGFP transgenic mouse.
    J Neurosci. 2004 Jul 21;24(29):6466-75 PMID: 15269256
  17. Homer: a protein that selectively binds metabotropic glutamate receptors.
    Nature. 1997 Mar 20;386(6622):284-8 PMID: 9069287
  18. Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors.
    Cell. 2003 Sep 19;114(6):777-89 PMID: 14505576
  19. Internalization of ionotropic glutamate receptors in response to mGluR activation.
    Nat Neurosci. 2001 Nov;4(11):1079-85 PMID: 11687813
  20. LTP saturation and spatial learning disruption: effects of task variables and saturation levels.
    J Neurosci. 1994 Oct;14(10):5793-806 PMID: 7931545
  21. Enzymatic degradation protects neurons from glutamate excitotoxicity.
    J Neurochem. 2000 Sep;75(3):1045-52 PMID: 10936185
  22. Homer regulates gain of ryanodine receptor type 1 channel complex.
    J Biol Chem. 2002 Nov 22;277(47):44722-30 PMID: 12223488
  23. Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors.
    Neuron. 2006 Nov 9;52(3):475-84 PMID: 17088213
  24. Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate.
    Neuron. 2008 Jul 10;59(1):84-97 PMID: 18614031
  25. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders.
    Nat Rev Drug Discov. 2009 Jan;8(1):41-54 PMID: 19116626
  26. Constitutive activity and inverse agonists of G protein-coupled receptors: a current perspective.
    Mol Pharmacol. 2003 Dec;64(6):1271-6 PMID: 14645655
  27. Direct interaction and functional coupling between metabotropic glutamate receptor subtype 1 and voltage-sensitive Cav2.1 Ca2+ channel.
    J Biol Chem. 2003 Jul 4;278(27):25101-8 PMID: 12704197
  28. Homer-dependent cell surface expression of metabotropic glutamate receptor type 5 in neurons.
    Mol Cell Neurosci. 2002 Jun;20(2):323-9 PMID: 12093163
  29. Tyrosine phosphorylation and regulation of the AMPA receptor by SRC family tyrosine kinases.
    J Neurosci. 2004 Jul 7;24(27):6152-60 PMID: 15240807
  30. Tyrosine dephosphorylation regulates AMPAR internalisation in mGluR-LTD.
    Mol Cell Neurosci. 2009 Feb;40(2):267-79 PMID: 19063969
  31. Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer.
    Nature. 2001 Jun 21;411(6840):962-5 PMID: 11418862
  32. The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmic binding proteins.
    Neuron. 1993 Jul;11(1):41-52 PMID: 8338667
  33. The tyrosine phosphatase STEP mediates AMPA receptor endocytosis after metabotropic glutamate receptor stimulation.
    J Neurosci. 2008 Oct 15;28(42):10561-6 PMID: 18923032
  34. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice.
    Nat Neurosci. 2001 Sep;4(9):873-4 PMID: 11528416
  35. Agonist-independent internalization of metabotropic glutamate receptor 1a is arrestin- and clathrin-dependent and is suppressed by receptor inverse agonists.
    J Neurochem. 2004 May;89(4):1009-20 PMID: 15140199
  36. Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking.
    Neuron. 2006 Nov 9;52(3):445-59 PMID: 17088211
  37. The non-competitive antagonists 2-methyl-6-(phenylethynyl)pyridine and 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester interact with overlapping binding pockets in the transmembrane region of group I metabotropic glutamate receptors.
    J Biol Chem. 2000 Oct 27;275(43):33750-8 PMID: 10934211
  38. Two distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells.
    Neuron. 1997 Jun;18(6):969-82 PMID: 9208864
  39. Therapeutic implications of the mGluR theory of fragile X mental retardation.
    Genes Brain Behav. 2005 Aug;4(6):393-8 PMID: 16098137
  40. Activation of a dimeric metabotropic glutamate receptor by intersubunit rearrangement.
    J Biol Chem. 2007 Nov 9;282(45):33000-8 PMID: 17855348
  41. Phosphorylation of Homer3 by calcium/calmodulin-dependent kinase II regulates a coupling state of its target molecules in Purkinje cells.
    J Neurosci. 2008 May 14;28(20):5369-82 PMID: 18480293
  42. Endogenous homer proteins regulate metabotropic glutamate receptor signaling in neurons.
    J Neurosci. 2008 Aug 20;28(34):8560-7 PMID: 18716215
  43. Rapid rise in transcription factor mRNAs in rat brain after electroshock-induced seizures.
    J Neurochem. 1990 Dec;55(6):1920-7 PMID: 2230801
Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
1097-4199
DOI
10.1016/j.neuron.2010.11.008
Published
2010-12-22
Pages
1128-42
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC3013614
Subset
IM
Grants
NIMH NIH HHS · P50 MH084020 · United States
NIDA NIH HHS · R37 DA010309 · United States
NIDA NIH HHS · DA010309 · United States
NINDS NIH HHS · R01 NS036715 · United States
NIDA NIH HHS · R01 DA010309 · United States
NIDA NIH HHS · R01 DA011742-13 · United States
NINDS NIH HHS · NS036715 · United States
NIMH NIH HHS · MH084020 · United States
NIDA NIH HHS · R37 DA010309-16 · United States
NIDA NIH HHS · R01 DA011742 · United States
NIDA NIH HHS · DA011742 · United States
External Links
PubMed source DOI: 10.1016/j.neuron.2010.11.008 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2