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Cited by 167Neuroscience and Neuropharmacology ResearchReceptor Mechanisms and SignalingNicotinic Acetylcholine Receptors Study

TARP Phosphorylation Regulates Synaptic AMPA Receptors through Lipid Bilayers

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Sumioka, Akio, Yan, Dan, Tomita, Susumu·2010·Neuron
DOI 10.1016/j.neuron.2010.04.035PMC PMC2887694
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Abstract

Neurons use neurotransmitters to communicate across synapses, constructing neural circuits in the brain. AMPA-type glutamate receptors are the predominant excitatory neurotransmitter receptors mediating fast synaptic transmission. AMPA receptors localize at synapses by forming protein complexes with transmembrane AMPA receptor regulatory proteins (TARPs) and PSD-95-like membrane-associated guanylate kinases. Among the three classes of ionotropic glutamate receptors (AMPA, NMDA, and kainate type), AMPA receptor activity is most regulatable by neuronal activity to adjust synaptic strength. Here, we mutated the prototypical TARP, stargazin, and found that TARP phosphorylation regulates synaptic AMPA receptor activity in vivo. We also found that stargazin interacts with negatively charged lipid bilayers in a phosphorylation-dependent manner and that the lipid interaction inhibited stargazin binding to PSD-95. Cationic lipids dissociated stargazin from lipid bilayers and enhanced synaptic AMPA receptor activity in a stargazin phosphorylation-dependent manner. Thus, TARP phosphorylation plays a critical role in regulating AMPA receptor-mediated synaptic transmission via a lipid bilayer interaction.

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Crossref · 10.1016/j.neuron.2010.04.035

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  • CaMKII phosphorylation of TARP serines neutralizes charge, releasing the CTD and providing access to the PDZ domains of PSD-95.

    “CaMKII phosphorylation of the serines neutralizes the charge, releasing the CTD and providing access to the PDZ domains of PSD-95 (284, 285, 287).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [285]

    The Discussion (‘Roles of multiple phosphorylation sites in TARPs’; page unavailable) says acidic phosphorylated serines inhibit the electrostatic interaction of stargazin’s basic residues with negatively charged lipid bilayers. The Results (‘Lipid bilayers inhibit binding of stargazin to PSD-95’; page unavailable) say phosphorylation permits dissociation from lipids and binding to PSD-95. Our copy does not identify CaMKII as the kinase responsible for this mechanism, so that attribution is unsupported. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 53

  1. Bats C Groc L Choquet D 2007 The interaction between Stargazin and PSD-95 regulates AMPA receptor surface trafficking Neuron 53 719 734 17329211
  2. Beique JC Andrade R 2003 PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex J Physiol 546 859 867 12563010 PMC2342599
  3. Cho CH St-Gelais F Zhang W Tomita S Howe JR 2007 Two Families of TARP Isoforms that Have Distinct Effects on the Kinetic Properties of AMPA Receptors and Synaptic Currents Neuron 55 890 904 17880893
  4. Cho KO Hunt CA Kennedy MB 1992 The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein Neuron 9 929 942 1419001
  5. Collingridge GL Isaac JT Wang YT 2004 Receptor trafficking and synaptic plasticity Nat Rev Neurosci 5 952 962 15550950
  6. Coombs ID Cull-Candy SG 2009 Transmembrane AMPA receptor regulatory proteins and AMPA receptor function in the cerebellum Neuroscience 162 656 665 19185052 PMC3217091
  7. Dakoji S Tomita S Karimzadegan S Nicoll RA Bredt DS 2003 Interaction of transmembrane AMPA receptor regulatory proteins with multiple membrane associated guanylate kinases Neuropharmacology 45 849 856 14529722
  8. Darios F Wasser C Shakirzyanova A Giniatullin A Goodman K Munoz-Bravo JL Raingo J Jorgacevski J Kreft M Zorec R 2009 Sphingosine facilitates SNARE complex assembly and activates synaptic vesicle exocytosis Neuron 62 683 694 19524527 PMC2697323
  9. Di Paolo G De Camilli P 2006 Phosphoinositides in cell regulation and membrane dynamics Nature 443 651 657 17035995
  10. Ehrlich I Malinow R 2004 Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity J Neurosci 24 916 927 14749436 PMC6729816
  11. Elias GM Funke L Stein V Grant SG Bredt DS Nicoll RA 2006 Synapse-Specific and Developmentally Regulated Targeting of AMPA Receptors by a Family of MAGUK Scaffolding Proteins Neuron 52 307 320 17046693
  12. Fukata Y Tzingounis AV Trinidad JC Fukata M Burlingame AL Nicoll RA Bredt DS 2005 Molecular constituents of neuronal AMPA receptors J Cell Biol 169 399 404 15883194 PMC2171936
  13. Hashimoto K Fukaya M Qiao X Sakimura K Watanabe M Kano M 1999 Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer J Neurosci 19 6027 6036 10407040 PMC6783074
  14. Inamura M Itakura M Okamoto H Hoka S Mizoguchi A Fukazawa Y Shigemoto R Yamamori S Takahashi M 2006 Differential localization and regulation of stargazin-like protein, gamma-8 and stargazin in the plasma membrane of hippocampal and cortical neurons Neurosci Res 55 45 53 16516319
  15. Jin W Ge WP Xu J Cao M Peng L Yung W Liao D Duan S Zhang M Xia J 2006 Lipid binding regulates synaptic targeting of PICK1, AMPA receptor trafficking, and synaptic plasticity J Neurosci 26 2380 2390 16510715 PMC6793652
  16. Kato AS Siuda ER Nisenbaum ES Bredt DS 2008 AMPA receptor subunit-specific regulation by a distinct family of type II TARPs Neuron 59 986 996 18817736
  17. Kato AS Zhou W Milstein AD Knierman MD Siuda ER Dotzlaf JE Yu H Hale JE Nisenbaum ES Nicoll RA 2007 New transmembrane AMPA receptor regulatory protein isoform, gamma-7, differentially regulates AMPA receptors J Neurosci 27 4969 4977 17475805 PMC6672084
  18. Kessels HW Kopec CD Klein ME Malinow R 2009 Roles of stargazin and phosphorylation in the control of AMPA receptor subcellular distribution Nat Neurosci 12 888 896 19543281 PMC3922706
  19. Kessels HW Malinow R 2009 Synaptic AMPA receptor plasticity and behavior Neuron 61 340 350 19217372 PMC3917551
  20. Kim KS Yan D Tomita S 2010 Assembly and stoichiometry of the AMPA receptor and transmembrane AMPA receptor regulatory protein complex J Neurosci 30 1064 1072 20089915 PMC2821155
  21. Kott S Werner M Korber C Hollmann M 2007 Electrophysiological properties of AMPA receptors are differentially modulated depending on the associated member of the TARP family J Neurosci 27 3780 3789 17409242 PMC6672393
  22. Lee HK Takamiya K Han JS Man H Kim CH Rumbaugh G Yu S Ding L He C Petralia RS 2003 Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory Cell 112 631 643 12628184
  23. Lisman J 2003 Long-term potentiation: outstanding questions and attempted synthesis Philos Trans R Soc Lond B Biol Sci 358 829 842 12740130 PMC1693147
  24. Malenka RC Bear MF 2004 LTP and LTD: an embarrassment of riches Neuron 44 5 21 15450156
  25. Menuz K Kerchner GA O’Brien JL Nicoll RA 2009 Critical role for TARPs in early development despite broad functional redundancy Neuropharmacology 56 22 29 18634809 PMC3111090
  26. Menuz K Stroud RM Nicoll RA Hays FA 2007 TARP Auxiliary Subunits Switch AMPA Receptor Antagonists into Partial Agonists Science 318 815 817 17975069
  27. Migaud M Charlesworth P Dempster M Webster LC Watabe AM Makhinson M He Y Ramsay MF Morris RG Morrison JH 1998 Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein Nature 396 433 439 9853749
  28. Milstein AD Zhou W Karimzadegan S Bredt DS Nicoll RA 2007 TARP Subtypes Differentially and Dose-Dependently Control Synaptic AMPA Receptor Gating Neuron 55 905 918 17880894 PMC3167227
  29. Nakagawa T Futai K Lashuel HA Lo I Okamoto K Walz T Hayashi Y Sheng M 2004 Quaternary structure, protein dynamics, and synaptic function of SAP97 controlled by L27 domain interactions Neuron 44 453 467 15504326
  30. Nelson SB Turrigiano GG 2008 Strength through diversity Neuron 60 477 482 18995822 PMC4919814
  31. Newpher TM Ehlers MD 2008 Glutamate receptor dynamics in dendritic microdomains Neuron 58 472 497 18498731 PMC2572138
  32. Nicoll RA Tomita S Bredt DS 2006 Auxiliary subunits assist AMPA-type glutamate receptors Science 311 1253 1256 16513974
  33. Osten P Stern-Bach Y 2006 Learning from stargazin: the mouse, the phenotype and the unexpected Curr Opin Neurobiol 16 275 280 16678401
  34. Pan L Wu H Shen C Shi Y Jin W Xia J Zhang M 2007 Clustering and synaptic targeting of PICK1 requires direct interaction between the PDZ domain and lipid membranes EMBO J 26 4576 4587 17914463 PMC2063473
  35. Priel A Kolleker A Ayalon G Gillor M Osten P Stern-Bach Y 2005 Stargazin reduces desensitization and slows deactivation of the AMPA-type glutamate receptors J Neurosci 25 2682 2686 15758178 PMC6725153
  36. Rouach N Byrd K Petralia RS Elias GM Adesnik H Tomita S Karimzadegan S Kealey C Bredt DS Nicoll RA 2005 TARP gamma-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity Nat Neurosci 8 1525 1533 16222232
  37. Sager C Tapken D Kott S Hollmann M 2009 Functional modulation of AMPA receptors by transmembrane AMPA receptor regulatory proteins Neuroscience 158 45 54 18304745
  38. Schluter OM Xu W Malenka RC 2006 Alternative N-terminal domains of PSD-95 and SAP97 govern activity-dependent regulation of synaptic AMPA receptor function Neuron 51 99 111 16815335
  39. Schnell E Sizemore M Karimzadegan S Chen L Bredt DS Nicoll RA 2002 Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number Proc Natl Acad Sci U S A 99 13902 13907 12359873 PMC129795
  40. Shepherd JD Huganir RL 2007 The Cell Biology of Synaptic Plasticity: AMPA Receptor Trafficking Annu Rev Cell Dev Biol 17506699
  41. Soto D Coombs ID Kelly L Farrant M Cull-Candy SG 2007 Stargazin attenuates intracellular polyamine block of calcium-permeable AMPA receptors Nat Neurosci 10 1260 1267 17873873 PMC2430330
  42. Tomita S Adesnik H Sekiguchi M Zhang W Wada K Howe JR Nicoll RA Bredt DS 2005a Stargazin modulates AMPA receptor gating and trafficking by distinct domains Nature 435 1052 1058 15858532
  43. Tomita S Chen L Kawasaki Y Petralia RS Wenthold RJ Nicoll RA Bredt DS 2003 Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins J Cell Biol 161 805 816 12771129 PMC2199354
  44. Tomita S Sekiguchi M Wada K Nicoll RA Bredt DS 2006 Stargazin controls the pharmacology of AMPA receptor potentiators Proc Natl Acad Sci U S A 103 10064 10067 16785437 PMC1502506
  45. Tomita S Stein V Stocker TJ Nicoll RA Bredt DS 2005b Bidirectional synaptic plasticity regulated by phosphorylation of stargazin-like TARPs Neuron 45 269 277 15664178
  46. Towler DA Gordon JI Adams SP Glaser L 1988 The biology and enzymology of eukaryotic protein acylation Annu Rev Biochem 57 69 99 3052287
  47. Tsui J Malenka RC 2006 Substrate localization creates specificity in calcium/calmodulin-dependent protein kinase II signaling at synapses J Biol Chem 281 13794 13804 16551613
  48. Turetsky D Garringer E Patneau DK 2005 Stargazin modulates native AMPA receptor functional properties by two distinct mechanisms J Neurosci 25 7438 7448 16093395 PMC6725298
  49. Vandenberghe W Nicoll RA Bredt DS 2005 Stargazin is an AMPA receptor auxiliary subunit Proc Natl Acad Sci U S A 102 485 490 15630087 PMC544314
  50. Venter JC Adams MD Myers EW Li PW Mural RJ Sutton GG Smith HO Yandell M Evans CA Holt RA 2001 The sequence of the human genome Science 291 1304 1351 11181995
  51. Wang R Walker CS Brockie PJ Francis MM Mellem JE Madsen DM Maricq AV 2008 Evolutionary conserved role for TARPs in the gating of glutamate receptors and tuning of synaptic function Neuron 59 997 1008 18817737 PMC2754846
  52. Yeung T Gilbert GE Shi J Silvius J Kapus A Grinstein S 2008 Membrane phosphatidylserine regulates surface charge and protein localization Science 319 210 213 18187657
  53. Ziff EB 2007 TARPs and the AMPA receptor trafficking paradox Neuron 53 627 633 17329203

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Authors
Sumioka, A., Yan, D., & Tomita, S.
Affiliations
Yale University (US)
Corresponding author
Tomita, Susumu
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2010-06
Volume
66
Issue
5
Pages
755-767
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2010.04.035
PMC
PMC2887694
OpenAlex
W1977873923
Cited by
167
References
5
Citations by year
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FWCI
5.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • University of California, San Diego
  • National Institute of Mental Health (MH077939, R01MH077939, R56MH077939)
  • National Institute on Drug Abuse (P30DA018343)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
stargazin, AMPA receptors, synaptic transmission, lipid bilayer interaction, PSD-95, ionotropic glutamate receptors, synaptic plasticity, cationic lipids
MeSH terms
Animals, Cricetulus, Cricetinae, Lipid Bilayers, Membrane Proteins, Mice, Mutant Strains, Phosphorylation, Synapses, Calcium Channels, CHO Cells, Receptors, AMPA, Mice, Gene Knock-In Techniques

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