Glutamate Receptor Auxiliary Subunits and Interacting Protein Partners in the Cerebellum

  • Ian D. Coombs
  • Stuart G. Cull-Candy


AMPA- and kainate-type glutamate receptors play a central role in excitatory signaling and synaptic plasticity in the cerebellum. Considerable attention has therefore focused on the molecular mechanisms involved in the dynamic control of these receptors and their constituent subunits. A number of transmembrane and intracellular proteins have emerged as key molecular determinants of AMPA and kainate receptor behavior.

Much of the early information on transmembrane AMPAR regulatory proteins (TARPs) arose from experiments on cerebellar neurons in stargazer mice. Although it is clear that the TARPs regulate AMPAR properties throughout the brain, the cerebellum continues to be a particularly suitable brain region for studies on the functional role of TARPs and many of the other receptor-associated proteins. This chapter focuses on the AMPA and kainate receptor subtypes and subunits present in the main cerebellar neurons and glia. In particular, we will consider recent evidence for the dynamic regulation of these receptor subunits by transmembrane and intracellular protein partners – in relation to cerebellar synaptic transmission and plasticity.


Purkinje Cell Kainate Receptor Bergmann Glia Auxiliary Subunit AMPAR Subunit 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We are grateful to the Wellcome Trust, the MRC and the Royal Society for support, and to our colleagues for invaluable discussions.


  1. Ahn S, Ginty DD, Linden DJ (1999) A late phase of cerebellar long-term depression requires activation of CaMKIV and CREB. Neuron 23:559–568PubMedCrossRefGoogle Scholar
  2. Arikkath J, Reichardt LF (2008) Cadherins and catenins at synapses: roles in synaptogenesis and synaptic plasticity. Trends Neurosci 31:487–494PubMedCrossRefGoogle Scholar
  3. Bahn S, Wisden W (1997) A map of non-NMDA receptor subunit expression in the vertebrate brain derived from in situ hybridization histochemistry. Humana Press, TotowaGoogle Scholar
  4. Banke TG, Bowie D, Lee H, Huganir RL, Schousboe A, Traynelis SF (2000) Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase. J Neurosci 20:89–102PubMedGoogle Scholar
  5. Bats C, Groc L, Choquet D (2007) The interaction between Stargazin and PSD-95 regulates AMPA receptor surface trafficking. Neuron 53:719–734PubMedCrossRefGoogle Scholar
  6. Bedoukian MA, Weeks AM, Partin KM (2006) Different domains of the AMPA receptor direct stargazin-mediated trafficking and stargazin-mediated modulation of kinetics. J Biol Chem 281:23908–23921PubMedCrossRefGoogle Scholar
  7. Belcher SM, Howe JR (1997) Characterization of RNA editing of the glutamate-receptor subunits GluR5 and GluR6 in granule cells during cerebellar development. Brain Res Mol Brain Res 52:130–138PubMedCrossRefGoogle Scholar
  8. Benson DL, Tanaka H (1998) N-cadherin redistribution during synaptogenesis in hippocampal neurons. J Neurosci 18:6892–6904PubMedGoogle Scholar
  9. Block MR, Glick BS, Wilcox CA, Wieland FT, Rothman JE (1988) Purification of an N-ethylmaleimide-sensitive protein catalyzing vesicular transport. Proc Natl Acad Sci USA 85:7852–7856PubMedCrossRefGoogle Scholar
  10. Bork P, Beckmann G (1993) The CUB domain. A widespread module in developmentally regulated proteins. J Mol Biol 231:539–545PubMedCrossRefGoogle Scholar
  11. Boulter J, Hollmann M, O’Shea-Greenfield A, Hartley M, Deneris E, Maron C, Heinemann S (1990) Molecular cloning and functional expression of glutamate receptor subunit genes. Science 249:1033–1037PubMedCrossRefGoogle Scholar
  12. Bredt DS, Nicoll RA (2003) AMPA receptor trafficking at excitatory synapses. Neuron 40:361–379PubMedCrossRefGoogle Scholar
  13. Brenman JE, Christopherson KS, Craven SE, McGee AW, Bredt DS (1996) Cloning and characterization of postsynaptic density 93, a nitric oxide synthase interacting protein. J Neurosci 16:7407–7415PubMedGoogle Scholar
  14. Brickley S, Swanson GT, Contractor A, Farrant M, Cull-Candy S, Heinemann S (1999) Functional GluR5-containing kainate receptors are restricted to extrasynaptic sites in Purkinje cells of the mouse cerebellum. J Physiol 521:90PGoogle Scholar
  15. Bureau I, Dieudonne S, Coussen F, Mulle C (2000) Kainate receptor-mediated synaptic currents in cerebellar Golgi cells are not shaped by diffusion of glutamate. Proc Natl Acad Sci USA 97:6838–6843PubMedCrossRefGoogle Scholar
  16. Burnashev N, Khodorova A, Jonas P, Helm PJ, Wisden W, Monyer H, Seeburg PH, Sakmann B (1992) Calcium-permeable AMPA-kainate receptors in fusiform cerebellar glial cells. Science 256:1566–1570PubMedCrossRefGoogle Scholar
  17. Cai C, Coleman SK, Niemi K, Keinanen K (2002) Selective binding of synapse-associated protein 97 to GluR-A alpha-amino-5-hydroxy-3-methyl-4-isoxazole propionate receptor subunit is determined by a novel sequence motif. J Biol Chem 277:31484–31490PubMedCrossRefGoogle Scholar
  18. Carter AG, Regehr WG (2000) Prolonged synaptic currents and glutamate spillover at the parallel fiber to stellate cell synapse. J Neurosci 20:4423–4434PubMedGoogle Scholar
  19. Cathala L, Brickley S, Cull-Candy S, Farrant M (2003) Maturation of EPSCs and intrinsic membrane properties enhances precision at a cerebellar synapse. J Neurosci 23:6074–6085PubMedGoogle Scholar
  20. Chen L, Bao S, Qiao X, Thompson RF (1999) Impaired cerebellar synapse maturation in waggler, a mutant mouse with a disrupted neuronal calcium channel gamma subunit. Proc Natl Acad Sci USA 96:12132–12137PubMedCrossRefGoogle Scholar
  21. Chen L, Chetkovich DM, Petralia RS, Sweeney NT, Kawasaki Y, Wenthold RJ, Bredt DS, Nicoll RA (2000) Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408:936–943PubMedCrossRefGoogle Scholar
  22. Chen L, El-Husseini A, Tomita S, Bredt DS, Nicoll RA (2003) Stargazin differentially controls the trafficking of alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate and kainate receptors. Mol Pharmacol 64:703–706PubMedCrossRefGoogle Scholar
  23. Chetkovich DM, Chen L, Stocker TJ, Nicoll RA, Bredt DS (2002) Phosphorylation of the postsynaptic density-95 (PSD-95)/discs large/zona occludens-1 binding site of stargazin regulates binding to PSD-95 and synaptic targeting of AMPA receptors. J Neurosci 22:5791–5796PubMedGoogle Scholar
  24. Choi J, Ko J, Park E, Lee JR, Yoon J, Lim S, Kim E (2002) Phosphorylation of stargazin by protein kinase A regulates its interaction with PSD-95. J Biol Chem 277:12359–12363PubMedCrossRefGoogle Scholar
  25. Chung HJ, Xia J, Scannevin RH, Zhang X, Huganir RL (2000) Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins. J Neurosci 20:7258–7267PubMedGoogle Scholar
  26. Chung HJ, Steinberg JP, Huganir RL, Linden DJ (2003) Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. Science 300:1751–1755PubMedCrossRefGoogle Scholar
  27. Clark BA, Cull-Candy SG (2002) Activity-dependent recruitment of extrasynaptic NMDA receptor activation at an AMPA receptor-only synapse. J Neurosci 22:4428–4436PubMedGoogle Scholar
  28. Coleman SK, Cai C, Kalkkinen N, Korpi ER, Keinanen K (2010) Analysis of the potential role of GluA4 carboxyl-terminus in PDZ interactions. PLoS One 5:e8715PubMedCrossRefGoogle Scholar
  29. Collingridge GL, Isaac JT (2003) Functional roles of protein interactions with AMPA and kainate receptors. Neurosci Res 47:3–15PubMedCrossRefGoogle Scholar
  30. Coombs ID, Cull-Candy SG (2009) Transmembrane AMPA receptor regulatory proteins and AMPA receptor function in the cerebellum. Neuroscience 162:656–665PubMedCrossRefGoogle Scholar
  31. Coussen F (2009) Molecular determinants of kainate receptor trafficking. Neuroscience 158:25–35PubMedCrossRefGoogle Scholar
  32. Coussen F, Perrais D, Jaskolski F, Sachidhanandam S, Normand E, Bockaert J, Marin P, Mulle C (2005) Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex. Neuron 47:555–566PubMedCrossRefGoogle Scholar
  33. Crepel F (2009) Role of presynaptic kainate receptors at parallel fiber-Purkinje cell synapses in induction of cerebellar LTD: interplay with climbing fiber input. J Neurophysiol 102:965–973PubMedCrossRefGoogle Scholar
  34. Crepel F, Dhanjal SS, Sears TA (1982) Effect of glutamate, aspartate and related derivatives on cerebellar Purkinje cell dendrites in the rat: an in vitro study. J Physiol 329:297–317PubMedGoogle Scholar
  35. Cull-Candy SG, Usowicz MM (1987) Multiple-conductance channels activated by excitatory amino acids in cerebellar neurons. Nature 325:525–528PubMedCrossRefGoogle Scholar
  36. Cull-Candy SG, Howe JR, Ogden DC (1988) Noise and single channels activated by excitatory amino acids in rat cerebellar granule neurones. J Physiol 400:189–222PubMedGoogle Scholar
  37. 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 45:849–856PubMedCrossRefGoogle Scholar
  38. Derkach V, Barria A, Soderling TR (1999) Ca2+/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors. Proc Natl Acad Sci USA 96:3269–3274PubMedCrossRefGoogle Scholar
  39. Dev KK, Nishimune A, Henley JM, Nakanishi S (1999) The protein kinase C alpha binding protein PICK1 interacts with short but not long form alternative splice variants of AMPA receptor subunits. Neuropharmacology 38:635–644PubMedCrossRefGoogle Scholar
  40. Dong H, O’Brien RJ, Fung ET, Lanahan AA, Worley PF, Huganir RL (1997) GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors. Nature 386:279–284PubMedCrossRefGoogle Scholar
  41. Engelman HS, MacDermott AB (2004) Presynaptic ionotropic receptors and control of transmitter release. Nat Rev Neurosci 5:135–145PubMedCrossRefGoogle Scholar
  42. Farrant M, Feldmeyer D, Takahashi T, Cull-Candy SG (1994) NMDA-receptor channel diversity in the developing cerebellum. Nature 368:335–339PubMedCrossRefGoogle Scholar
  43. Ferkany JW, Coyle JT (1983) Kainic acid selectively stimulates the release of endogenous excitatory acidic amino acids. J Pharmacol Exp Ther 225:399–406PubMedGoogle Scholar
  44. Ferkany JW, Zaczek R, Coyle JT (1982) Kainic acid stimulates excitatory amino acid neurotransmitter release at presynaptic receptors. Nature 298:757–759PubMedCrossRefGoogle Scholar
  45. Fukaya M, Yamazaki M, Sakimura K, Watanabe M (2005) Spatial diversity in gene expression for VDCCgamma subunit family in developing and adult mouse brains. Neurosci Res 53:376–383PubMedCrossRefGoogle Scholar
  46. Gallo V, Suergiu R, Levi G (1987) Functional evaluation of glutamate receptor subtypes in cultured cerebellar neurones and astrocytes. Eur J Pharmacol 138:293–297PubMedCrossRefGoogle Scholar
  47. Garcia EP, Mehta S, Blair LA, Wells DG, Shang J, Fukushima T, Fallon JR, Garner CC, Marshall J (1998) SAP90 binds and clusters kainate receptors causing incomplete desensitization. Neuron 21:727–739PubMedCrossRefGoogle Scholar
  48. Gardner SM, Takamiya K, Xia J, Suh JG, Johnson R, Yu S, Huganir RL (2005) Calcium-permeable AMPA receptor plasticity is mediated by subunit-specific interactions with PICK1 and NSF. Neuron 45:903–915PubMedCrossRefGoogle Scholar
  49. Garthwaite J, Garthwaite G (1983) The mechanism of kainic acid neurotoxicity. Nature 305:138–140PubMedCrossRefGoogle Scholar
  50. Gill MB, Kato AS, Roberts MF, Yu H, Wang H, Tomita S, Bredt DS (2011) Cornichon-2 modulates AMPA receptor–transmembrane AMPA receptor regulatory protein assembly to dictate gating and pharmacology. J Neurosci 31:6928–6938PubMedCrossRefGoogle Scholar
  51. Gliem M, Weisheit G, Mertz KD, Endl E, Oberdick J, Schilling K (2006) Expression of classical cadherins in the cerebellar anlage: quantitative and functional aspects. Mol Cell Neurosci 33:447–458PubMedCrossRefGoogle Scholar
  52. Greger IH, Akamine P, Khatri L, Ziff EB (2006) Developmentally regulated, combinatorial RNA processing modulates AMPA receptor biogenesis. Neuron 51:85–97PubMedCrossRefGoogle Scholar
  53. Hansel C, Linden DJ, D’Angelo E (2001) Beyond parallel fiber LTD: the diversity of synaptic and non-synaptic plasticity in the cerebellum. Nat Neurosci 4:467–475PubMedGoogle Scholar
  54. 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 19:6027–6036PubMedGoogle Scholar
  55. Higuchi M, Single FN, Kohler M, Sommer B, Sprengel R, Seeburg PH (1993) RNA editing of AMPA receptor subunit GluR-B: a base-paired intron-exon structure determines position and efficiency. Cell 75:1361–1370PubMedCrossRefGoogle Scholar
  56. Hirbec H, Francis JC, Lauri SE, Braithwaite SP, Coussen F, Mulle C, Dev KK, Coutinho V, Meyer G, Isaac JT et al (2003) Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP. Neuron 37:625–638PubMedCrossRefGoogle Scholar
  57. Huang YH, Dykes-Hoberg M, Tanaka K, Rothstein JD, Bergles DE (2004) Climbing fiber activation of EAAT4 transporters and kainate receptors in cerebellar Purkinje cells. J Neurosci 24:103–111PubMedCrossRefGoogle Scholar
  58. Huang Y, Man HY, Sekine-Aizawa Y, Han Y, Juluri K, Luo H, Cheah J, Lowenstein C, Huganir RL, Snyder SH (2005) S-nitrosylation of N-ethylmaleimide sensitive factor mediates surface expression of AMPA receptors. Neuron 46:533–540PubMedCrossRefGoogle Scholar
  59. Iino M, Goto K, Kakegawa W, Okado H, Sudo M, Ishiuchi S, Miwa A, Takayasu Y, Saito I, Tsuzuki K et al (2001) Glia-synapse interaction through Ca2+ − permeable AMPA receptors in Bergmann glia. Science 292:926–929PubMedCrossRefGoogle Scholar
  60. Ito M (2001) Cerebellar long-term depression: characterization, signal transduction, and functional roles. Physiol Rev 81:1143–1195PubMedGoogle Scholar
  61. Jaskolski F, Coussen F, Nagarajan N, Normand E, Rosenmund C, Mulle C (2004) Subunit composition and alternative splicing regulate membrane delivery of kainate receptors. J Neurosci 24:2506–2515PubMedCrossRefGoogle Scholar
  62. Jungling K, Eulenburg V, Moore R, Kemler R, Lessmann V, Gottmann K (2006) N-cadherin transsynaptically regulates short-term plasticity at glutamatergic synapses in embryonic stem cell-derived neurons. J Neurosci 26:6968–6978PubMedCrossRefGoogle Scholar
  63. Kalashnikova E, Lorca RA, Kaur I, Barisone GA, Li B, Ishimaru T, Trimmer JS, Mohapatra DP, Diaz E (2010) SynDIG1: an activity-regulated, AMPA- receptor-interacting transmembrane protein that regulates excitatory synapse development. Neuron 65:80–93PubMedCrossRefGoogle Scholar
  64. Kano M, Kato M (1987) Quisqualate receptors are specifically involved in cerebellar synaptic plasticity. Nature 325:276–279PubMedCrossRefGoogle Scholar
  65. Kato AS, Zhou W, Milstein AD, Knierman MD, Siuda ER, Dotzlaf JE, Yu H, Hale JE, Nisenbaum ES, Nicoll RA et al (2007) New transmembrane AMPA receptor regulatory protein isoform, gamma-7, differentially regulates AMPA receptors. J Neurosci 27:4969–4977PubMedCrossRefGoogle Scholar
  66. Kato AS, Siuda ER, Nisenbaum ES, Bredt DS (2008) AMPA receptor subunit-specific regulation by a distinct family of type II TARPs. Neuron 59:986–996PubMedCrossRefGoogle Scholar
  67. Kato AS, Gill MB, Ho MT, Yu H, Tu Y, Siuda ER, Wang H, Qian YW, Nisenbaum ES, Tomita S, Bredt DS (2010) Hippocampal AMPA receptor gating controlled by both TARP and cornichon proteins. Neuron 68:1082–1096PubMedCrossRefGoogle Scholar
  68. Kawasaki H, Fujii H, Gotoh Y, Morooka T, Shimohama S, Nishida E, Hirano T (1999) Requirement for mitogen-activated protein kinase in cerebellar long term depression. J Biol Chem 274:13498–13502PubMedCrossRefGoogle Scholar
  69. Keinanen K, Wisden W, Sommer B, Werner P, Herb A, Verdoorn TA, Sakmann B, Seeburg PH (1990) A family of AMPA-selective glutamate receptors. Science 249:556–560PubMedCrossRefGoogle Scholar
  70. Kelly L, Farrant M, Cull-Candy SG (2009) Synaptic mGluR activation drives plasticity of calcium-permeable AMPA receptors. Nat Neurosci 12:593–601PubMedCrossRefGoogle Scholar
  71. Kim CH, Lisman JE (2001) A labile component of AMPA receptor-mediated synaptic transmission is dependent on microtubule motors, actin, and N-ethylmaleimide-sensitive factor. J Neurosci 21:4188–4194PubMedGoogle Scholar
  72. Kimura H, Okamoto K, Sakai Y (1985) Pharmacological characterization of postsynaptic receptors for excitatory amino acids in Purkinje cell dendrites in the guinea pig cerebellum. c 8:119–127Google Scholar
  73. Kinney GA, Overstreet LS, Slater NT (1997) Prolonged physiological entrapment of glutamate in the synaptic cleft of cerebellar unipolar brush cells. J Neurophysiol 78:1320–1333PubMedGoogle Scholar
  74. Kistner U, Wenzel BM, Veh RW, Cases-Langhoff C, Garner AM, Appeltauer U, Voss B, Gundelfinger ED, Garner CC (1993) SAP90, a rat presynaptic protein related to the product of the Drosophila tumor suppressor gene dlg-A. J Biol Chem 268:4580–4583PubMedGoogle Scholar
  75. Kohler M, Burnashev N, Sakmann B, Seeburg PH (1993) Determinants of Ca2+ permeability in both TM1 and TM2 of high affinity kainate receptor channels: diversity by RNA editing. Neuron 10:491–500PubMedCrossRefGoogle Scholar
  76. Kohler M, Kornau HC, Seeburg PH (1994) The organization of the gene for the functionally dominant alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit GluR-B. J Biol Chem 269:17367–17370PubMedGoogle Scholar
  77. Korber C, Werner M, Kott S, Ma ZL, Hollmann M (2007) The transmembrane AMPA receptor regulatory protein gamma 4 is a more effective modulator of AMPA receptor function than stargazin (gamma 2). J Neurosci 27:8442–8447PubMedCrossRefGoogle Scholar
  78. Kuroda S, Schweighofer N, Kawato M (2001) Exploration of signal transduction pathways in cerebellar long-term depression by kinetic simulation. J Neurosci 21:5693–5702PubMedGoogle Scholar
  79. Laezza F, Wilding TJ, Sequeira S, Coussen F, Zhang XZ, Hill-Robinson R, Mulle C, Huettner JE, Craig AM (2007) KRIP6: a novel BTB/Kelch protein regulating function of kainate receptors. Mol Cell Neurosci 34:539–550PubMedCrossRefGoogle Scholar
  80. Laezza F, Wilding TJ, Sequeira S, Craig AM, Huettner JE (2008) The BTB/kelch protein, KRIP6, modulates the interaction of PICK1 with GluR6 kainate receptors. Neuropharmacology 55:1131–1139PubMedCrossRefGoogle Scholar
  81. Lee CJ, Bardoni R, Tong CK, Engelman HS, Joseph DJ, Magherini PC, MacDermott AB (2002) Functional expression of AMPA receptors on central terminals of rat dorsal root ganglion neurons and presynaptic inhibition of glutamate release. Neuron 35:135–146PubMedCrossRefGoogle Scholar
  82. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS, Brockway KS, Byrnes EJ et al (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168–176PubMedCrossRefGoogle Scholar
  83. Leonard AS, Davare MA, Horne MC, Garner CC, Hell JW (1998) SAP97 is associated with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit. J Biol Chem 273:19518–19524PubMedCrossRefGoogle Scholar
  84. Lerma J, Paternain AV, Rodriguez-Moreno A, Lopez-Garcia JC (2001) Molecular physiology of kainate receptors. Physiol Rev 81:971–998PubMedGoogle Scholar
  85. Letts VA, Felix R, Biddlecome GH, Arikkath J, Mahaffey CL, Valenzuela A, Bartlett FS 2nd, Mori Y, Campbell KP, Frankel WN (1998) The mouse stargazer gene encodes a neuronal Ca2+ −channel gamma subunit. Nat Genet 19:340–347PubMedCrossRefGoogle Scholar
  86. Lin SC, Bergles DE (2002) Physiological characteristics of NG2-expressing glial cells. J Neurocytol 31:537–549PubMedCrossRefGoogle Scholar
  87. Linden DJ (2001) The expression of cerebellar LTD in culture is not associated with changes in AMPA-receptor kinetics, agonist affinity, or unitary conductance. Proc Natl Acad Sci USA 98:14066–14071PubMedCrossRefGoogle Scholar
  88. Liu SQ, Cull-Candy SG (2000) Synaptic activity at calcium-permeable AMPA receptors induces a switch in receptor subtype. Nature 405:454–458PubMedCrossRefGoogle Scholar
  89. Liu SJ, Cull-Candy SG (2002) Activity-dependent change in AMPA receptor properties in cerebellar stellate cells. J Neurosci 22:3881–3889PubMedGoogle Scholar
  90. Liu SJ, Cull-Candy SG (2005) Subunit interaction with PICK and GRIP controls Ca2+ permeability of AMPARs at cerebellar synapses. Nat Neurosci 8:768–775PubMedCrossRefGoogle Scholar
  91. Liu SJ, Lachamp P (2006) The activation of excitatory glutamate receptors evokes a long-lasting increase in the release of GABA from cerebellar stellate cells. J Neurosci 26:9332–9339PubMedCrossRefGoogle Scholar
  92. Lu W, Ziff EB (2005) PICK1 interacts with ABP/GRIP to regulate AMPA receptor trafficking. Neuron 47:407–421PubMedCrossRefGoogle Scholar
  93. Mah SJ, Cornell E, Mitchell NA, Fleck MW (2005) Glutamate receptor trafficking: endoplasmic reticulum quality control involves ligand binding and receptor function. J Neurosci 25:2215–2225PubMedCrossRefGoogle Scholar
  94. Menuz K, Nicoll RA (2008) Loss of inhibitory neuron AMPA receptors contributes to ataxia and epilepsy in stargazer mice. J Neurosci 28:10599–10603PubMedCrossRefGoogle Scholar
  95. Menuz K, Stroud RM, Nicoll RA, Hays FA (2007) TARP auxiliary subunits switch AMPA receptor antagonists into partial agonists. Science 318:815–817PubMedCrossRefGoogle Scholar
  96. Menuz K, O’Brien JL, Karmizadegan S, Bredt DS, Nicoll RA (2008) TARP redundancy is critical for maintaining AMPA receptor function. J Neurosci 28:8740–8746PubMedCrossRefGoogle Scholar
  97. Misra C, Brickley SG, Farrant M, Cull-Candy SG (2000a) Identification of subunits contributing to synaptic and extrasynaptic NMDA receptors in Golgi cells of the rat cerebellum. J Physiol 524(Pt 1):147–162PubMedCrossRefGoogle Scholar
  98. Misra C, Brickley SG, Wyllie DJ, Cull-Candy SG (2000b) Slow deactivation kinetics of NMDA receptors containing NR1 and NR2D subunits in rat cerebellar Purkinje cells. J Physiol 525(Pt 2):299–305PubMedCrossRefGoogle Scholar
  99. Misra C, Restituito S, Ferreira J, Rameau GA, Fu J, Ziff EB (2010) Regulation of synaptic structure and function by palmitoylated AMPA receptor binding protein. Mol Cell Neurosci 43:341–352PubMedCrossRefGoogle Scholar
  100. Momiyama A, Feldmeyer D, Cull-Candy SG (1996) Identification of a native low-conductance NMDA channel with reduced sensitivity to Mg2+ in rat central neurones. J Physiol 494(Pt 2):479–492PubMedGoogle Scholar
  101. Morimoto-Tomita M, Zhang W, Straub C, Cho CH, Kim KS, Howe JR, Tomita S (2009) Autoinactivation of neuronal AMPA receptors via glutamate-regulated TARP interaction. Neuron 61:101–112PubMedCrossRefGoogle Scholar
  102. Muller BM, Kistner U, Veh RW, Cases-Langhoff C, Becker B, Gundelfinger ED, Garner CC (1995) Molecular characterization and spatial distribution of SAP97, a novel presynaptic protein homologous to SAP90 and the Drosophila discs-large tumor suppressor protein. J Neurosci 15:2354–2366PubMedGoogle Scholar
  103. Muller BM, Kistner U, Kindler S, Chung WJ, Kuhlendahl S, Fenster SD, Lau LF, Veh RW, Huganir RL, Gundelfinger ED et al (1996) SAP102, a novel postsynaptic protein that interacts with NMDA receptor complexes in vivo. Neuron 17:255–265PubMedCrossRefGoogle Scholar
  104. Murase S, Mosser E, Schuman EM (2002) Depolarization drives beta-Catenin into neuronal spines promoting changes in synaptic structure and function. Neuron 35:91–105PubMedCrossRefGoogle Scholar
  105. Ng D, Pitcher GM, Szilard RK, Sertie A, Kanisek M, Clapcote SJ, Lipina T, Kalia LV, Joo D, McKerlie C et al (2009) Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning. PLoS Biol 7:e41PubMedCrossRefGoogle Scholar
  106. Nishimune A, Isaac JT, Molnar E, Noel J, Nash SR, Tagaya M, Collingridge GL, Nakanishi S, Henley JM (1998) NSF binding to GluR2 regulates synaptic transmission. Neuron 21:87–97PubMedCrossRefGoogle Scholar
  107. Noel J, Ralph GS, Pickard L, Williams J, Molnar E, Uney JB, Collingridge GL, Henley JM (1999) Surface expression of AMPA receptors in hippocampal neurons is regulated by an NSF-dependent mechanism. Neuron 23:365–376PubMedCrossRefGoogle Scholar
  108. Nuriya M, Huganir RL (2006) Regulation of AMPA receptor trafficking by N-cadherin. J Neurochem 97:652–661PubMedCrossRefGoogle Scholar
  109. Ochiishi T, Futai K, Okamoto K, Kameyama K, Kosik KS (2008) Regulation of AMPA receptor trafficking by delta-catenin. Mol Cell Neurosci 39:499–507PubMedCrossRefGoogle Scholar
  110. Ogasawara H, Doi T, Kawato M (2008) Systems biology perspectives on cerebellar long-term depression. Neurosignals 16:300–317PubMedCrossRefGoogle Scholar
  111. Okamoto K, Sekiguchi M (1991) Synaptic receptors and intracellular signal transduction in the cerebellum. Neurosci Res 9:213–237PubMedCrossRefGoogle Scholar
  112. Opazo P, Choquet D (2011) A three-step model for the synaptic recruitment of AMPA receptors. Mol Cell Neurosci 46:1–8PubMedCrossRefGoogle Scholar
  113. Opazo P, Labrecque S, Tigaret CM, Frouin A, Wiseman PW, De Koninck P, Choquet D (2010) CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of stargazin. Neuron 67:239–252PubMedCrossRefGoogle Scholar
  114. Osten P, Srivastava S, Inman GJ, Vilim FS, Khatri L, Lee LM, States BA, Einheber S, Milner TA, Hanson PI et al (1998) The AMPA receptor GluR2 C terminus can mediate a reversible, ATP-dependent interaction with NSF and alpha- and beta-SNAPs. Neuron 21:99–110PubMedCrossRefGoogle Scholar
  115. Park C, Falls W, Finger JH, Longo-Guess CM, Ackerman SL (2002) Deletion in Catna2, encoding alpha N-catenin, causes cerebellar and hippocampal lamination defects and impaired startle modulation. Nat Genet 31:279–284PubMedGoogle Scholar
  116. Pemberton KE, Belcher SM, Ripellino JA, Howe JR (1998) High-affinity kainate-type ion channels in rat cerebellar granule cells. J Physiol 510(Pt 2):401–420PubMedCrossRefGoogle Scholar
  117. Penn AC, Williams SR, Greger IH (2008) Gating motions underlie AMPA receptor secretion from the endoplasmic reticulum. EMBO J 27:3056–3068PubMedCrossRefGoogle Scholar
  118. Perrais D, Coussen F, Mulle C (2009) Atypical functional properties of GluK3-containing kainate receptors. J Neurosci 29:15499–15510PubMedCrossRefGoogle Scholar
  119. Perrais D, Veran J, Mulle C (2010) Gating and permeation of kainate receptors: differences unveiled. Trends Pharmacol Sci 31:516–522PubMedCrossRefGoogle Scholar
  120. Pertz O, Bozic D, Koch AW, Fauser C, Brancaccio A, Engel J (1999) A new crystal structure, Ca2+ dependence and mutational analysis reveal molecular details of E-cadherin homoassociation. EMBO J 18:1738–1747PubMedCrossRefGoogle Scholar
  121. Poncer JC, Esteban JA, Malinow R (2002) Multiple mechanisms for the potentiation of AMPA receptor-mediated transmission by alpha-Ca2+/calmodulin-dependent protein kinase II. J Neurosci 22:4406–4411PubMedGoogle Scholar
  122. Porter RH, Eastwood SL, Harrison PJ (1997) Distribution of kainate receptor subunit mRNAs in human hippocampus, neocortex and cerebellum, and bilateral reduction of hippocampal GluR6 and KA2 transcripts in schizophrenia. Brain Res 751:217–231PubMedCrossRefGoogle Scholar
  123. Renzi M, Farrant M, Cull-Candy SG (2007) Climbing-fibre activation of NMDA receptors in Purkinje cells of adult mice. J Physiol 585:91–101PubMedCrossRefGoogle Scholar
  124. Rieger S, Senghaas N, Walch A, Koster RW (2009) Cadherin-2 controls directional chain migration of cerebellar granule neurons. PLoS Biol 7:e1000240PubMedCrossRefGoogle Scholar
  125. Rivera R, Rozas JL, Lerma J (2007) PKC-dependent autoregulation of membrane kainate receptors. EMBO J 26:4359–4367PubMedCrossRefGoogle Scholar
  126. Rossi B, Maton G, Collin T (2008) Calcium-permeable presynaptic AMPA receptors in cerebellar molecular layer interneurones. J Physiol 586:5129–5145PubMedCrossRefGoogle Scholar
  127. Rozas JL, Paternain AV, Lerma J (2003) Noncanonical signaling by ionotropic kainate receptors. Neuron 39:543–553PubMedCrossRefGoogle Scholar
  128. Rusakov DA, Fine A (2003) Extracellular Ca2+ depletion contributes to fast activity-dependent modulation of synaptic transmission in the brain. Neuron 37:287–297PubMedCrossRefGoogle Scholar
  129. Rusakov DA, Saitow F, Lehre KP, Konishi S (2005) Modulation of presynaptic Ca2+ entry by AMPA receptors at individual GABAergic synapses in the cerebellum. J Neurosci 25:4930–4940PubMedCrossRefGoogle Scholar
  130. Sager C, Tapken D, Hollmann M (2010) The C-terminal domains of TARPs: unexpectedly versatile domains. Channels (Austin) 4:155–158CrossRefGoogle Scholar
  131. Saglietti L, Dequidt C, Kamieniarz K, Rousset MC, Valnegri P, Thoumine O, Beretta F, Fagni L, Choquet D, Sala C et al (2007) Extracellular interactions between GluR2 and N-cadherin in spine regulation. Neuron 54:461–477PubMedCrossRefGoogle Scholar
  132. Sakurai M (1987) Synaptic modification of parallel fibre-Purkinje cell transmission in in vitro guinea-pig cerebellar slices. J Physiol 394:463–480PubMedGoogle Scholar
  133. Salinas GD, Blair LA, Needleman LA, Gonzales JD, Chen Y, Li M, Singer JD, Marshall J (2006) Actinfilin is a Cul3 substrate adaptor, linking GluR6 kainate receptor subunits to the ubiquitin-proteasome pathway. J Biol Chem 281:40164–40173PubMedCrossRefGoogle Scholar
  134. Santos SD, Manadas B, Duarte CB, Carvalho AL (2010) Proteomic analysis of an interactome for long-form AMPA receptor subunits. J Proteome Res 9:1670–1682PubMedCrossRefGoogle Scholar
  135. Schmolesky MT, De Ruiter MM, De Zeeuw CI, Hansel C (2007) The neuropeptide corticotropin-releasing factor regulates excitatory transmission and plasticity at the climbing fibre-Purkinje cell synapse. Eur J Neurosci 25:1460–1466PubMedCrossRefGoogle Scholar
  136. Schwenk J, Harmel N, Zolles G, Bildl W, Kulik A, Heimrich B, Chisaka O, Jonas P, Schulte U, Fakler B et al (2009) Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors. Science 323:1313–1319PubMedCrossRefGoogle Scholar
  137. Selvakumar B, Huganir RL, Snyder SH (2009) S-nitrosylation of stargazin regulates surface expression of AMPA-glutamate neurotransmitter receptors. Proc Natl Acad Sci USA 106:16440–16445PubMedCrossRefGoogle Scholar
  138. Sharpey-Schafer E (1929) The essentials of histology. Longmans, Green, LondonGoogle Scholar
  139. Shi S, Hayashi Y, Esteban JA, Malinow R (2001) Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell 105:331–343PubMedCrossRefGoogle Scholar
  140. Shi Y, Suh YH, Milstein AD, Isozaki K, Schmid SM, Roche KW, Nicoll RA (2010) Functional comparison of the effects of TARPs and cornichons on AMPA receptor trafficking and gating. Proc Natl Acad Sci USA 107:16315–16319PubMedCrossRefGoogle Scholar
  141. Shin JH, Linden DJ (2005) An NMDA receptor/nitric oxide cascade is involved in cerebellar LTD but is not localized to the parallel fiber terminal. J Neurophysiol 94:4281–4289PubMedCrossRefGoogle Scholar
  142. Silver RA, Traynelis SF, Cull-Candy SG (1992) Rapid-time-course miniature and evoked excitatory currents at cerebellar synapses in situ. Nature 355:163–166PubMedCrossRefGoogle Scholar
  143. Silverman JB, Restituito S, Lu W, Lee-Edwards L, Khatri L, Ziff EB (2007) Synaptic anchorage of AMPA receptors by cadherins through neural plakophilin-related arm protein AMPA receptor-binding protein complexes. J Neurosci 27:8505–8516PubMedCrossRefGoogle Scholar
  144. Smith TC, Wang LY, Howe JR (1999) Distinct kainate receptor phenotypes in immature and mature mouse cerebellar granule cells. J Physiol 517(Pt 1):51–58PubMedCrossRefGoogle Scholar
  145. Sommer B, Keinanen K, Verdoorn TA, Wisden W, Burnashev N, Herb A, Kohler M, Takagi T, Sakmann B, Seeburg PH (1990) Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS. Science 249:1580–1585PubMedCrossRefGoogle Scholar
  146. Sommer B, Kohler M, Sprengel R, Seeburg PH (1991) RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67:11–19PubMedCrossRefGoogle Scholar
  147. Sommer B, Burnashev N, Verdoorn TA, Keinanen K, Sakmann B, Seeburg PH (1992) A glutamate receptor channel with high affinity for domoate and kainate. EMBO J 11:1651–1656PubMedGoogle Scholar
  148. Song I, Kamboj S, Xia J, Dong H, Liao D, Huganir RL (1998) Interaction of the N-ethylmaleimide-sensitive factor with AMPA receptors. Neuron 21:393–400PubMedCrossRefGoogle Scholar
  149. Soto D, Coombs ID, Kelly L, Farrant M, Cull-Candy SG (2007) Stargazin attenuates intracellular polyamine block of calcium-permeable AMPA receptors. Nat Neurosci 10:1260–1267PubMedCrossRefGoogle Scholar
  150. Soto D, Coombs ID, Renzi M, Zonouzi M, Farrant M, Cull-Candy SG (2009) Selective regulation of long-form calcium-permeable AMPA receptors by an atypical TARP, gamma-5. Nat Neurosci 12:277–285PubMedCrossRefGoogle Scholar
  151. Srivastava S, Osten P, Vilim FS, Khatri L, Inman G, States B, Daly C, DeSouza S, Abagyan R, Valtschanoff JG et al (1998) Novel anchorage of GluR2/3 to the postsynaptic density by the AMPA receptor-binding protein ABP. Neuron 21:581–591PubMedCrossRefGoogle Scholar
  152. Staudinger J, Lu J, Olson EN (1997) Specific interaction of the PDZ domain protein PICK1 with the COOH terminus of protein kinase C-alpha. J Biol Chem 272:32019–32024PubMedCrossRefGoogle Scholar
  153. Stein EL, Chetkovich DM (2010) Regulation of stargazin synaptic trafficking by C-terminal PDZ ligand phosphorylation in bidirectional synaptic plasticity. J Neurochem 113:42–53PubMedCrossRefGoogle Scholar
  154. Steinberg JP, Huganir RL, Linden DJ (2004) N-ethylmaleimide-sensitive factor is required for the synaptic incorporation and removal of AMPA receptors during cerebellar long-term depression. Proc Natl Acad Sci USA 101:18212–18216PubMedCrossRefGoogle Scholar
  155. Steinberg JP, Takamiya K, Shen Y, Xia J, Rubio ME, Yu S, Jin W, Thomas GM, Linden DJ, Huganir RL (2006) Targeted in vivo mutations of the AMPA receptor subunit GluR2 and its interacting protein PICK1 eliminate cerebellar long-term depression. Neuron 49:845–860PubMedCrossRefGoogle Scholar
  156. Stogios PJ, Prive GG (2004) The BACK domain in BTB-kelch proteins. Trends Biochem Sci 29:634–637PubMedCrossRefGoogle Scholar
  157. Sumioka A, Yan D, Tomita S (2010) TARP phosphorylation regulates synaptic AMPA receptors through lipid bilayers. Neuron 66:755–767PubMedCrossRefGoogle Scholar
  158. Suzuki SC, Takeichi M (2008) Cadherins in neuronal morphogenesis and function. Dev Growth Differ 50(Suppl 1):S119–S130PubMedCrossRefGoogle Scholar
  159. Swanson GT, Feldmeyer D, Kaneda M, Cull-Candy SG (1996) Effect of RNA editing and subunit co-assembly single-channel properties of recombinant kainate receptors. J Physiol 492(Pt 1):129–142PubMedGoogle Scholar
  160. Swanson GT, Kamboj SK, Cull-Candy SG (1997) Single-channel properties of recombinant AMPA receptors depend on RNA editing, splice variation, and subunit composition. J Neurosci 17:58–69PubMedGoogle Scholar
  161. Szapiro G, Barbour B (2007) Multiple climbing fibers signal to molecular layer interneurons exclusively via glutamate spillover. Nat Neurosci 10:735–742PubMedCrossRefGoogle Scholar
  162. Tai CY, Mysore SP, Chiu C, Schuman EM (2007) Activity-regulated N-cadherin endocytosis. Neuron 54:771–785PubMedCrossRefGoogle Scholar
  163. Tai CY, Kim SA, Schuman EM (2008) Cadherins and synaptic plasticity. Curr Opin Cell Biol 20:567–575PubMedCrossRefGoogle Scholar
  164. Takeichi M, Inuzuka H, Shimamura K, Matsunaga M, Nose A (1990) Cadherin-mediated cell-cell adhesion and neurogenesis. Neurosci Res Suppl 13:S92–S96PubMedCrossRefGoogle Scholar
  165. Tang L, Hung CP, Schuman EM (1998) A role for the cadherin family of cell adhesion molecules in hippocampal long-term potentiation. Neuron 20:1165–1175PubMedCrossRefGoogle Scholar
  166. 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 161:805–816PubMedCrossRefGoogle Scholar
  167. Tomita S, Fukata M, Nicoll RA, Bredt DS (2004) Dynamic interaction of stargazin-like TARPs with cycling AMPA receptors at synapses. Science 303:1508–1511PubMedCrossRefGoogle Scholar
  168. 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 435:1052–1058PubMedCrossRefGoogle Scholar
  169. Tomita S, Stein V, Stocker TJ, Nicoll RA, Bredt DS (2005b) Bidirectional synaptic plasticity regulated by phosphorylation of stargazin-like TARPs. Neuron 45:269–277PubMedCrossRefGoogle Scholar
  170. Traynelis SF, Wahl P (1997) Control of rat GluR6 glutamate receptor open probability by protein kinase A and calcineurin. J Physiol 503(Pt 3):513–531PubMedCrossRefGoogle Scholar
  171. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62:405–496PubMedCrossRefGoogle Scholar
  172. Turetsky D, Garringer E, Patneau DK (2005) Stargazin modulates native AMPA receptor functional properties by two distinct mechanisms. J Neurosci 25:7438–7448PubMedCrossRefGoogle Scholar
  173. von Engelhardt J, Mack V, Sprengel R, Kavenstock N, Li KW, Stern-Bach Y, Smit AB, Seeburg PH, Monyer H (2010) CKAMP44: a brain-specific protein attenuating short-term synaptic plasticity in the dentate gyrus. Science 327:1518–1522CrossRefGoogle Scholar
  174. Walker CS, Brockie PJ, Madsen DM, Francis MM, Zheng Y, Koduri S, Mellem JE, Strutz-Seebohm N, Maricq AV (2006) Reconstitution of invertebrate glutamate receptor function depends on stargazin-like proteins. Proc Natl Acad Sci USA 103:10781–10786PubMedCrossRefGoogle Scholar
  175. Wisden W, Seeburg PH (1993) A complex mosaic of high-affinity kainate receptors in rat brain. J Neurosci 13:3582–3598PubMedGoogle Scholar
  176. Wyllie DJ, Mathie A, Symonds CJ, Cull-Candy SG (1991) Activation of glutamate receptors and glutamate uptake in identified macroglial cells in rat cerebellar cultures. J Physiol 432:235–258PubMedGoogle Scholar
  177. Wyszynski M, Valtschanoff JG, Naisbitt S, Dunah AW, Kim E, Standaert DG, Weinberg R, Sheng M (1999) Association of AMPA receptors with a subset of glutamate receptor-interacting protein in vivo. J Neurosci 19:6528–6537PubMedGoogle Scholar
  178. Xia J, Zhang X, Staudinger J, Huganir RL (1999) Clustering of AMPA receptors by the synaptic PDZ domain-containing protein PICK1. Neuron 22:179–187PubMedCrossRefGoogle Scholar
  179. Xia J, Chung HJ, Wihler C, Huganir RL, Linden DJ (2000) Cerebellar long-term depression requires PKC-regulated interactions between GluR2/3 and PDZ domain-containing proteins. Neuron 28:499–510PubMedCrossRefGoogle Scholar
  180. Xue F, Cooley L (1993) kelch encodes a component of intercellular bridges in Drosophila egg chambers. Cell 72:681–693PubMedCrossRefGoogle Scholar
  181. Yamazaki M, Fukaya M, Hashimoto K, Yamasaki M, Tsujita M, Itakura M, Abe M, Natsume R, Takahashi M, Kano M et al (2010) TARPs gamma-2 and gamma-7 are essential for AMPA receptor expression in the cerebellum. Eur J Neurosci 31:2204–2220PubMedCrossRefGoogle Scholar
  182. Zhang W, St-Gelais F, Grabner CP, Trinidad JC, Sumioka A, Morimoto-Tomita M, Kim KS, Straub C, Burlingame AL, Howe JR et al (2009) A transmembrane accessory subunit that modulates kainate-type glutamate receptors. Neuron 61:385–396PubMedCrossRefGoogle Scholar
  183. Zhao C, Slevin JT, Whiteheart SW (2007) Cellular functions of NSF: not just SNAPs and SNAREs. FEBS Lett 581:2140–2149PubMedCrossRefGoogle Scholar
  184. Zheng Y, Mellem JE, Brockie PJ, Madsen DM, Maricq AV (2004) SOL-1 is a CUB-domain protein required for GLR-1 glutamate receptor function in C. elegans. Nature 427:451–457PubMedCrossRefGoogle Scholar
  185. Ziff EB (2007) TARPs and the AMPA receptor trafficking paradox. Neuron 53:627–633PubMedCrossRefGoogle Scholar
  186. Zollman S, Godt D, Prive GG, Couderc JL, Laski FA (1994) The BTB domain, found primarily in zinc finger proteins, defines an evolutionarily conserved family that includes several developmentally regulated genes in Drosophila. Proc Natl Acad Sci USA 91:10717–10721PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of Neuroscience, Physiology and PharmacologyUniversity College LondonLondonUK

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