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Diverse roles for auxiliary subunits in phosphorylation-dependent regulation of mammalian brain voltage-gated potassium channels

Abstract

Voltage-gated ion channels are a diverse family of signaling proteins that mediate rapid electrical signaling events. Among these, voltage-gated potassium or Kv channels are the most diverse partly due to the large number of principal (or α) subunits and auxiliary subunits that can assemble in different combinations to generate Kv channel complexes with distinct structures and functions. The diversity of Kv channels underlies much of the variability in the active properties between different mammalian central neurons and the dynamic changes that lead to experience-dependent plasticity in intrinsic excitability. Recent studies have revealed that Kv channel α subunits and auxiliary subunits are extensively phosphorylated, contributing to additional structural and functional diversity. Here, we highlight recent studies that show that auxiliary subunits exert some of their profound effects on dendritic Kv4 and axonal Kv1 channels through phosphorylation-dependent mechanisms, either due to phosphorylation on the auxiliary subunit itself or by influencing the extent and/or impact of α subunit phosphorylation. The complex effects of auxiliary subunits and phosphorylation provide a potent mechanism to generate additional diversity in the structure and function of Kv4 and Kv1 channels, as well as allowing for dynamic reversible regulation of these important ion channels.

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References

  1. Adams JP, Anderson AE, Varga AW, Dineley KT, Cook RG, Pfaffinger PJ, Sweatt JD (2000) The A-type potassium channel Kv4.2 is a substrate for the mitogen-activated protein kinase ERK. J Neurochem 75:2277–87

    PubMed  CAS  Article  Google Scholar 

  2. An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS, Rhodes KJ (2000) Modulation of A-type potassium channels by a family of calcium sensors. Nature 403:553–6

    PubMed  CAS  Article  Google Scholar 

  3. Anderson AE, Adams JP, Qian Y, Cook RG, Pfaffinger PJ, Sweatt JD (2000) Kv4.2 phosphorylation by cyclic AMP-dependent protein kinase. J Biol Chem 275:5337–46

    PubMed  CAS  Article  Google Scholar 

  4. Andrasfalvy BK, Makara JK, Johnston D, Magee JC (2008) Altered synaptic and non-synaptic properties of CA1 pyramidal neurons in Kv4.2 knockout mice. J Physiol 586:3881–92

    PubMed  CAS  Article  Google Scholar 

  5. Baek JH, Cerda O, Trimmer JS (2011) Mass spectrometry-based phosphoproteomics reveals multisite phosphorylation on mammalian brain voltage-gated sodium and potassium channels. Semin Cell Dev Biol 22:153–9

    PubMed  CAS  Article  Google Scholar 

  6. Barnwell LF, Lugo JN, Lee WL, Willis SE, Gertz SJ, Hrachovy RA, Anderson AE (2009) Kv4.2 knockout mice demonstrate increased susceptibility to convulsant stimulation. Epilepsia 50:1741–51

    PubMed  CAS  Article  Google Scholar 

  7. Bernard C, Anderson A, Becker A, Poolos NP, Beck H, Johnston D (2004) Acquired dendritic channelopathy in temporal lobe epilepsy. Science 305:532–5

    PubMed  CAS  Article  Google Scholar 

  8. Bourdeau ML, Laplante I, Laurent CE, Lacaille JC (2011) KChIP1 modulation of Kv4.3-mediated A-type K(+) currents and repetitive firing in hippocampal interneurons. Neuroscience 176:173–87

    PubMed  CAS  Article  Google Scholar 

  9. Brew HM, Gittelman JX, Silverstein RS, Hanks TD, Demas VP, Robinson LC, Robbins CA, McKee-Johnson J, Chiu SY, Messing A, Tempel BL (2007) Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons. J Neurophysiol 98:1501–25

    PubMed  CAS  Article  Google Scholar 

  10. Cachero TG, Morielli AD, Peralta EG (1998) The small GTP-binding protein RhoA regulates a delayed rectifier potassium channel. Cell 93:1077–85

    PubMed  CAS  Article  Google Scholar 

  11. Campomanes CR, Carroll KI, Manganas LN, Hershberger ME, Gong B, Antonucci DE, Rhodes KJ, Trimmer JS (2002) Kv beta subunit oxidoreductase activity and Kv1 potassium channel trafficking. J Biol Chem 277:8298–305

    PubMed  CAS  Article  Google Scholar 

  12. Cerda O, Trimmer JS (2010) Analysis and functional implications of phosphorylation of neuronal voltage-gated potassium channels. Neurosci Lett 486:60–7

    PubMed  CAS  Article  Google Scholar 

  13. Chen X, Yuan LL, Zhao C, Birnbaum SG, Frick A, Jung WE, Schwarz TL, Sweatt JD, Johnston D (2006) Deletion of Kv4.2 gene eliminates dendritic A-type K+ current and enhances induction of long-term potentiation in hippocampal CA1 pyramidal neurons. J Neurosci 26:12143–51

    PubMed  CAS  Article  Google Scholar 

  14. Clark BD, Kwon E, Maffie J, Jeong HY, Nadal M, Strop P, Rudy B (2008) DPP6 localization in brain supports function as a Kv4 channel associated protein. Front Mol Neurosci 1:8

    PubMed  Article  CAS  Google Scholar 

  15. Colbert CM, Pan E (1999) Arachidonic acid reciprocally alters the availability of transient and sustained dendritic K(+) channels in hippocampal CA1 pyramidal neurons. J Neurosci 19:8163–71

    PubMed  CAS  Google Scholar 

  16. Coleman SK, Newcombe J, Pryke J, Dolly JO (1999) Subunit composition of Kv1 channels in human CNS. J Neurochem 73:849–58

    PubMed  CAS  Article  Google Scholar 

  17. Connor JX, McCormack K, Pletsch A, Gaeta S, Ganetzky B, Chiu SY, Messing A (2005) Genetic modifiers of the Kv beta2-null phenotype in mice. Genes Brain Behav 4:77–88

    PubMed  CAS  Google Scholar 

  18. Connors EC, Ballif BA, Morielli AD (2008) Homeostatic regulation of Kv1.2 potassium channel trafficking by cyclic AMP. J Biol Chem 283:3445–53

    PubMed  CAS  Article  Google Scholar 

  19. Croci C, Brandstatter JH, Enz R (2003) ZIP3, a new splice variant of the PKC-zeta-interacting protein family, binds to GABAC receptors, PKC-zeta, and Kv beta 2. J Biol Chem 278:6128–35

    PubMed  CAS  Article  Google Scholar 

  20. Debanne D, Campanac E, Bialowas A, Carlier E, Alcaraz G (2011) Axon physiology. Physiol Rev 91:555–602

    PubMed  CAS  Article  Google Scholar 

  21. Dell'Acqua ML, Smith KE, Gorski JA, Horne EA, Gibson ES, Gomez LL (2006) Regulation of neuronal PKA signaling through AKAP targeting dynamics. Eur J Cell Biol 85:627–33

    PubMed  Article  CAS  Google Scholar 

  22. Giese KP, Storm JF, Reuter D, Fedorov NB, Shao LR, Leicher T, Pongs O, Silva AJ (1998) Reduced K+ channel inactivation, spike broadening, and after-hyperpolarization in Kvbeta1.1-deficient mice with impaired learning. Learn Mem 5:257–73

    PubMed  CAS  Google Scholar 

  23. Gong J, Xu J, Bezanilla M, van Huizen R, Derin R, Li M (1999) Differential stimulation of PKC phosphorylation of potassium channels by ZIP1 and ZIP2. Science 285:1565–9

    PubMed  CAS  Article  Google Scholar 

  24. Gu Y, Gu C (2010) Dynamics of Kv1 channel transport in axons. PLoS One 5:e11931

    PubMed  Article  CAS  Google Scholar 

  25. Gu C, Gu Y (2011) Clustering and activity tuning of Kv1 channels in myelinated hippocampal axons. J Biol Chem

  26. Gu C, Jan YN, Jan LY (2003) A conserved domain in axonal targeting of Kv1 (Shaker) voltage-gated potassium channels. Science 301:646–9

    PubMed  CAS  Article  Google Scholar 

  27. Gu C, Zhou W, Puthenveedu MA, Xu M, Jan YN, Jan LY (2006) The microtubule plus-end tracking protein EB1 is required for Kv1 voltage-gated K+ channel axonal targeting. Neuron 52:803–16

    PubMed  CAS  Article  Google Scholar 

  28. Gulbis JM, Mann S, MacKinnon R (1999) Structure of a voltage-dependent K+ channel beta subunit. Cell 97:943–52

    PubMed  CAS  Article  Google Scholar 

  29. Gulbis JM, Zhou M, Mann S, MacKinnon R (2000) Structure of the cytoplasmic beta subunit-T1 assembly of voltage- dependent K+ channels. Science 289:123–7

    PubMed  CAS  Article  Google Scholar 

  30. Hammond RS, Lin L, Sidorov MS, Wikenheiser AM, Hoffman DA (2008) Protein kinase a mediates activity-dependent Kv4.2 channel trafficking. J Neurosci 28:7513–9

    PubMed  CAS  Article  Google Scholar 

  31. Hasdemir B, Fitzgerald DJ, Prior IA, Tepikin AV, Burgoyne RD (2005) Traffic of Kv4 K+ channels mediated by KChIP1 is via a novel post-ER vesicular pathway. J Cell Biol 171:459–69

    PubMed  CAS  Article  Google Scholar 

  32. Heilstedt HA, Burgess DL, Anderson AE, Chedrawi A, Tharp B, Lee O, Kashork CD, Starkey DE, Wu YQ, Noebels JL, Shaffer LG, Shapira SK (2001) Loss of the potassium channel beta-subunit gene, KCNAB2, is associated with epilepsy in patients with 1p36 deletion syndrome. Epilepsia 42:1103–11

    PubMed  CAS  Article  Google Scholar 

  33. Hille B (2001) Ionic channels of excitable membranes, 3rd edn. Sinauer, Sunderland

    Google Scholar 

  34. Hoffman DA, Johnston D (1998) Downregulation of transient K+channels in dendrites of hippocampal CA1 pyramidal neurons by activation of PKA and PKC. J Neurosci 18:3521–8

    PubMed  CAS  Google Scholar 

  35. Holmqvist MH, Cao J, Knoppers MH, Jurman ME, Distefano PS, Rhodes KJ, Xie Y, An WF (2001) Kinetic modulation of Kv4-mediated A-current by arachidonic acid is dependent on potassium channel interacting proteins. J Neurosci 21:4154–61

    PubMed  CAS  Google Scholar 

  36. Jerng HH, Pfaffinger PJ, Covarrubias M (2004) Molecular physiology and modulation of somatodendritic A-type potassium channels. Mol Cell Neurosci 27:343–69

    PubMed  CAS  Article  Google Scholar 

  37. Johnson RP, El-Yazbi AF, Hughes MF, Schriemer DC, Walsh EJ, Walsh MP, Cole WC (2009) Identification and functional characterization of protein kinase A-catalyzed phosphorylation of potassium channel Kv1.2 at serine 449. J Biol Chem 284:16562–74

    PubMed  CAS  Article  Google Scholar 

  38. Johnston J, Forsythe ID, Kopp-Scheinpflug C (2010) Going native: voltage-gated potassium channels controlling neuronal excitability. J Physiol 588:3187–200

    PubMed  CAS  Article  Google Scholar 

  39. Judge SI, Bever CT Jr (2006) Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment. Pharmacol Ther 111:224–59

    PubMed  CAS  Article  Google Scholar 

  40. Kanyshkova T, Broicher T, Meuth SG, Pape HC, Budde T (2011) A-type K+ currents in intralaminar thalamocortical relay neurons. Pflugers Arch 461:545–56

    PubMed  CAS  Article  Google Scholar 

  41. Kim J, Jung SC, Clemens AM, Petralia RS, Hoffman DA (2007) Regulation of dendritic excitability by activity-dependent trafficking of the A-type K+ channel subunit Kv4.2 in hippocampal neurons. Neuron 54:933–47

    PubMed  CAS  Article  Google Scholar 

  42. Kim J, Nadal MS, Clemens AM, Baron M, Jung SC, Misumi Y, Rudy B, Hoffman DA (2008) Kv4 accessory protein DPPX (DPP6) is a critical regulator of membrane excitability in hippocampal CA1 pyramidal neurons. J Neurophysiol 100:1835–47

    PubMed  CAS  Article  Google Scholar 

  43. Kin Y, Misumi Y, Ikehara Y (2001) Biosynthesis and characterization of the brain-specific membrane protein DPPX, a dipeptidyl peptidase IV-related protein. J Biochem (Tokyo) 129:289–95

    CAS  Google Scholar 

  44. Klassen T, Davis C, Goldman A, Burgess D, Chen T, Wheeler D, McPherson J, Bourquin T, Lewis L, Villasana D, Morgan M, Muzny D, Gibbs R, Noebels J (2011) Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Cell 145:1036–48

    PubMed  CAS  Article  Google Scholar 

  45. Kwak YG, Hu N, Wei J, George AL Jr, Grobaski TD, Tamkun MM, Murray KT (1999) Protein kinase A phosphorylation alters Kvbeta1.3 subunit-mediated inactivation of the Kv1.5 potassium channel. J Biol Chem 274:13928–32

    PubMed  CAS  Article  Google Scholar 

  46. Lee L, Chen KC, Chang LS (2009) Functional roles of EF-hands in human potassium channel-interacting protein 2.2. Protein Pept Lett 16:1081–7

    PubMed  CAS  Article  Google Scholar 

  47. Lilliehook C, Bozdagi O, Yao J, Gomez-Ramirez M, Zaidi NF, Wasco W, Gandy S, Santucci AC, Haroutunian V, Huntley GW, Buxbaum JD (2003) Altered Abeta formation and long-term potentiation in a calsenilin knock-out. J Neurosci 23:9097–106

    PubMed  CAS  Google Scholar 

  48. Lin L, Sun W, Kung F, Dell'Acqua ML, Hoffman DA (2011) AKAP79/150 impacts intrinsic excitability of hippocampal neurons through phospho-regulation of A-type K+ channel trafficking. J Neurosci 31:1323–32

    PubMed  CAS  Article  Google Scholar 

  49. Lin L, Sun W, Wikenheiser AM, Kung F, Hoffman DA (2010) KChIP4a regulates Kv4.2 channel trafficking through PKA phosphorylation. Mol Cell Neurosci 43:315–25

    PubMed  CAS  Article  Google Scholar 

  50. Long SB, Campbell EB, Mackinnon R (2005) Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science 309:897–903

    PubMed  CAS  Article  Google Scholar 

  51. Losonczy A, Makara JK, Magee JC (2008) Compartmentalized dendritic plasticity and input feature storage in neurons. Nature 452:436–41

    PubMed  CAS  Article  Google Scholar 

  52. Lugo JN, Barnwell LF, Ren Y, Lee WL, Johnston LD, Kim R, Hrachovy RA, Sweatt JD, Anderson AE (2008) Altered phosphorylation and localization of the A-type channel, Kv4.2 in status epilepticus. J Neurochem 106:1929–40

    PubMed  CAS  Article  Google Scholar 

  53. Maffie J, Rudy B (2008) Weighing the evidence for a ternary protein complex mediating A-type K+ currents in neurons. J Physiol 586:5609–23

    PubMed  CAS  Article  Google Scholar 

  54. Makara JK, Losonczy A, Wen Q, Magee JC (2009) Experience-dependent compartmentalized dendritic plasticity in rat hippocampal CA1 pyramidal neurons. Nat Neurosci 12:1485–7

    PubMed  CAS  Article  Google Scholar 

  55. Marionneau C, Townsend RR, Nerbonne JM (2011) Proteomic analysis highlights the molecular complexities of native Kv4 channel macromolecular complexes. Semin Cell Dev Biol 22:145–52

    PubMed  CAS  Article  Google Scholar 

  56. McCormack K, Connor JX, Zhou L, Ho LL, Ganetzky B, Chiu SY, Messing A (2002) Genetic analysis of the mammalian K+ channel beta subunit Kvbeta 2 (Kcnab2). J Biol Chem 277:13219–28

    PubMed  CAS  Article  Google Scholar 

  57. McCormack T, McCormack K (1994) Shaker K+ channel beta subunits belong to an NAD(P)H-dependent oxidoreductase superfamily. Cell 79:1133–5

    PubMed  CAS  Article  Google Scholar 

  58. Menegola M, Misonou H, Vacher H, Trimmer JS (2008) Dendritic A-type potassium channel subunit expression in CA1 hippocampal interneurons. Neuroscience 154:953–64

    PubMed  CAS  Article  Google Scholar 

  59. Menegola M, Trimmer JS (2006) Unanticipated region- and cell-specific downregulation of individual KChIP auxiliary subunit isotypes in Kv4.2 knock-out mouse brain. J Neurosci 26:12137–42

    PubMed  CAS  Article  Google Scholar 

  60. Monaghan MM, Menegola M, Vacher H, Rhodes KJ, Trimmer JS (2008) Altered expression and localization of hippocampal A-type potassium channel subunits in the pilocarpine-induced model of temporal lobe epilepsy. Neuroscience 156:550–62

    PubMed  CAS  Article  Google Scholar 

  61. Monaghan MM, Trimmer JS, Rhodes KJ (2001) Experimental localization of Kv1 family voltage-gated K+ channel alpha and beta subunits in rat hippocampal formation. J Neurosci 21:5973–83

    PubMed  CAS  Google Scholar 

  62. Nadal MS, Ozaita A, Amarillo Y, Vega-Saenz de Miera E, Ma Y, Mo W, Goldberg EM, Misumi Y, Ikehara Y, Neubert TA, Rudy B (2003) The CD26-related dipeptidyl aminopeptidase-like protein DPPX is a critical component of neuronal A-type K+ channels. Neuron 37:449–61

    PubMed  CAS  Article  Google Scholar 

  63. Nadin BM, Pfaffinger PJ (2010) Dipeptidyl peptidase-like protein 6 is required for normal electrophysiological properties of cerebellar granule cells. J Neurosci 30:8551–65

    PubMed  CAS  Article  Google Scholar 

  64. Nagaya N, Papazian DM (1997) Potassium channel alpha and beta subunits assemble in the endoplasmic reticulum. J Biol Chem 272:3022–3027

    PubMed  CAS  Article  Google Scholar 

  65. Nakamura TY, Coetzee WA, Vega-Saenz De Miera E, Artman M, Rudy B (1997) Modulation of Kv4 channels, key components of rat ventricular transient outward K+ current, by PKC. Am J Physiol 273:H1775–86

    PubMed  CAS  Google Scholar 

  66. Need AC, Irvine EE, Giese KP (2003) Learning and memory impairments in Kv beta 1.1-null mutants are rescued by environmental enrichment or ageing. Eur J Neurosci 18:1640–4

    PubMed  Article  Google Scholar 

  67. Nesti E, Everill B, Morielli AD (2004) Endocytosis as a mechanism for tyrosine kinase-dependent suppression of a voltage-gated potassium channel. Mol Biol Cell 15:4073–88

    PubMed  CAS  Article  Google Scholar 

  68. Norris AJ, Foeger NC, Nerbonne JM (2010) Interdependent roles for accessory KChIP2, KChIP3, and KChIP4 subunits in the generation of Kv4-encoded IA channels in cortical pyramidal neurons. J Neurosci 30:13644–55

    PubMed  CAS  Article  Google Scholar 

  69. Pan Y, Weng J, Levin EJ, Zhou M (2011) Oxidation of NADPH on Kvbeta1 inhibits ball-and-chain type inactivation by restraining the chain. Proc Natl Acad Sci U S A 108:5885–90

    PubMed  CAS  Article  Google Scholar 

  70. Papazian DM (1999) Potassium channels: some assembly required. Neuron 23:7–10

    PubMed  CAS  Article  Google Scholar 

  71. Parcej DN, Dolly JO (1989) Elegance persists in the purification of K+ channels. Biochem J 264:623–4

    PubMed  CAS  Google Scholar 

  72. Perkowski JJ, Murphy GG (2011) Deletion of the mouse homolog of KCNAB2, a gene linked to monosomy 1p36, results in associative memory impairments and amygdala hyperexcitability. J Neurosci 31:46–54

    PubMed  CAS  Article  Google Scholar 

  73. Pongs O, Leicher T, Berger M, Roeper J, Bahring R, Wray D, Giese KP, Silva AJ, Storm JF (1999) Functional and molecular aspects of voltage-gated K+ channel beta subunits. Ann NY Acad Sci 868:344–355

    PubMed  CAS  Article  Google Scholar 

  74. Rasband MN, Trimmer JS (2009) Ion channel localization in axons. In: Squire LR (ed) Encyclopedia of neuroscience. Academic Press, Oxford, pp 229–235

    Chapter  Google Scholar 

  75. Rettig J, Heinemann SH, Wunder F, Lorra C, Parcej DN, Dolly JO, Pongs O (1994) Inactivation properties of voltage-gated K+ channels altered by presence of beta-subunit. Nature 369:289–294

    PubMed  CAS  Article  Google Scholar 

  76. Rhodes KJ, Carroll KI, Sung MA, Doliveira LC, Monaghan MM, Burke SL, Strassle BW, Buchwalder L, Menegola M, Cao J, An WF, Trimmer JS (2004) KChIPs and Kv4 alpha subunits as integral components of A-type potassium channels in mammalian brain. J Neurosci 24:7903–15

    PubMed  CAS  Article  Google Scholar 

  77. Rhodes KJ, Keilbaugh SA, Barrezueta NX, Lopez KL, Trimmer JS (1995) Association and colocalization of K+ channel alpha- and beta-subunit polypeptides in rat brain. J Neurosci 15:5360–71

    PubMed  CAS  Google Scholar 

  78. Rhodes KJ, Monaghan MM, Barrezueta NX, Nawoschik S, Bekele-Arcuri Z, Matos MF, Nakahira K, Schechter LE, Trimmer JS (1996) Voltage-gated K+ channel beta subunits: expression and distribution of Kv beta 1 and Kv beta 2 in adult rat brain. J Neurosci 16:4846–60

    PubMed  CAS  Google Scholar 

  79. Rhodes KJ, Strassle BW, Monaghan MM, Bekele-Arcuri Z, Matos MF, Trimmer JS (1997) Association and colocalization of the Kvbeta1 and Kvbeta2 beta-subunits with Kv1 alpha-subunits in mammalian brain K+ channel complexes. J Neurosci 17:8246–58

    PubMed  CAS  Google Scholar 

  80. Rivera J, Chu PJ, Lewis TL Jr, Arnold DB (2007) The role of Kif5B in axonal localization of Kv1 K(+) channels. Eur J Neurosci 25:136–46

    PubMed  Article  Google Scholar 

  81. Roeper J, Lorra C, Pongs O (1997) Frequency-dependent inactivation of mammalian A-type K+ channel KV1.4 regulated by Ca2+/calmodulin-dependent protein kinase. J Neurosci 17:3379–91

    PubMed  CAS  Google Scholar 

  82. Rosenkranz JA, Frick A, Johnston D (2009) Kinase-dependent modification of dendritic excitability after long-term potentiation. J Physiol 587:115–25

    PubMed  CAS  Article  Google Scholar 

  83. Ryan DP, Ptacek LJ (2010) Episodic neurological channelopathies. Neuron 68:282–92

    PubMed  CAS  Article  Google Scholar 

  84. Sanderson JL, Dell'Acqua ML (2011) AKAP signaling complexes in regulation of excitatory synaptic plasticity. Neuroscientist 17:321–36

    PubMed  CAS  Article  Google Scholar 

  85. Schrader LA, Anderson AE, Mayne A, Pfaffinger PJ, Sweatt JD (2002) PKA modulation of Kv4.2-encoded A-type potassium channels requires formation of a supramolecular complex. J Neurosci 22:10123–33

    PubMed  CAS  Google Scholar 

  86. Schrader LA, Birnbaum SG, Nadin BM, Ren Y, Bui D, Anderson AE, Sweatt JD (2006) ERK/MAPK regulates the Kv4.2 potassium channel by direct phosphorylation of the pore-forming subunit. Am J Physiol Cell Physiol 290:C852–61

    PubMed  CAS  Article  Google Scholar 

  87. Schrader LA, Ren Y, Cheng F, Bui D, Sweatt JD, Anderson AE (2009) Kv4.2 is a locus for PKC and ERK/MAPK cross-talk. Biochem J 417:705–15

    PubMed  CAS  Article  Google Scholar 

  88. Schulte U, Muller CS, Fakler B (2011) Ion channels and their molecular environments—glimpses and insights from functional proteomics. Semin Cell Dev Biol 22:132–44

    PubMed  CAS  Article  Google Scholar 

  89. Scott VE, Rettig J, Parcej DN, Keen JN, Findlay JB, Pongs O, Dolly JO (1994) Primary structure of a beta subunit of alpha-dendrotoxin-sensitive K+ channels from bovine brain. Proc Natl Acad Sci USA 91:1637–1641

    PubMed  CAS  Article  Google Scholar 

  90. Seikel E, Trimmer JS (2009) Convergent modulation of Kv4.2 channel alpha subunits by structurally distinct DPPX and KChIP auxiliary subunits. Biochemistry 48:5721–30

    PubMed  CAS  Article  Google Scholar 

  91. Sewing S, Roeper J, Pongs O (1996) Kv beta 1 subunit binding specific for shaker-related potassium channel alpha subunits. Neuron 16:455–463

    PubMed  CAS  Article  Google Scholar 

  92. Shah MM, Hammond RS, Hoffman DA (2010) Dendritic ion channel trafficking and plasticity. Trends Neurosci 33:307–16

    PubMed  CAS  Article  Google Scholar 

  93. Shapira SK, McCaskill C, Northrup H, Spikes AS, Elder FF, Sutton VR, Korenberg JR, Greenberg F, Shaffer LG (1997) Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome. Am J Hum Genet 61:642–50

    PubMed  CAS  Article  Google Scholar 

  94. Shi G, Nakahira K, Hammond S, Rhodes KJ, Schechter LE, Trimmer JS (1996) Beta subunits promote K+ channel surface expression through effects early in biosynthesis. Neuron 16:843–52

    PubMed  CAS  Article  Google Scholar 

  95. Shibata R, Misonou H, Campomanes CR, Anderson AE, Schrader LA, Doliveira LC, Carroll KI, Sweatt JD, Rhodes KJ, Trimmer JS (2003) A fundamental role for KChIPs in determining the molecular properties and trafficking of Kv4.2 potassium channels. J Biol Chem 278:36445–54

    PubMed  CAS  Article  Google Scholar 

  96. Singh B, Ogiwara I, Kaneda M, Tokonami N, Mazaki E, Baba K, Matsuda K, Inoue Y, Yamakawa K (2006) A Kv4.2 truncation mutation in a patient with temporal lobe epilepsy. Neurobiol Dis 24:245–53

    PubMed  CAS  Article  Google Scholar 

  97. Smart SL, Lopantsev V, Zhang CL, Robbins CA, Wang H, Chiu SY, Schwartzkroin PA, Messing A, Tempel BL (1998) Deletion of the K(V)1.1 potassium channel causes epilepsy in mice. Neuron 20:809–19

    PubMed  CAS  Article  Google Scholar 

  98. Strassle BW, Menegola M, Rhodes KJ, Trimmer JS (2005) Light and electron microscopic analysis of KChIP and Kv4 localization in rat cerebellar granule cells. J Comp Neurol 484:144–55

    PubMed  Article  Google Scholar 

  99. Tipparaju SM, Liu SQ, Barski OA, Bhatnagar A (2007) NADPH binding to beta-subunit regulates inactivation of voltage-gated K(+) channels. Biochem Biophys Res Commun 359:269–76

    PubMed  CAS  Article  Google Scholar 

  100. Trimmer JS (1998) Regulation of ion channel expression by cytoplasmic subunits. Curr Opin Neurobiol 8:370–4

    PubMed  CAS  Article  Google Scholar 

  101. Vacher H, Mohapatra DP, Trimmer JS (2008) Localization and targeting of voltage-dependent ion channels in mammalian central neurons. Physiol Rev 88:1407–47

    PubMed  CAS  Article  Google Scholar 

  102. Vacher H, Yang JW, Cerda O, Autillo-Touati A, Dargent B, Trimmer JS (2011) CDK-mediated phosphorylation of the Kv{beta}2 auxiliary subunit regulates Kv1 channel axonal targeting. J Cell Biol 192:813–24

    PubMed  CAS  Article  Google Scholar 

  103. Varga AW, Yuan LL, Anderson AE, Schrader LA, Wu GY, Gatchel JR, Johnston D, Sweatt JD (2004) Calcium-calmodulin-dependent kinase II modulates Kv4.2 channel expression and upregulates neuronal A-type potassium currents. J Neurosci 24:3643–54

    PubMed  CAS  Article  Google Scholar 

  104. Veh RW, Lichtinghagen R, Sewing S, Wunder F, Grumbach IM, Pongs O (1995) Immunohistochemical localization of five members of the Kv1 channel subunits: contrasting subcellular locations and neuron-specific co-localizations in rat brain. Eur J Neurosci 7:2189–2205

    PubMed  CAS  Article  Google Scholar 

  105. Wang X, Zhang J, Berkowski SM, Knowleg H, Chandramouly AB, Downens M, Prystowsky MB (2004) Protein kinase C-mediated phosphorylation of Kv beta 2 in adult rat brain. Neurochem Res 29:1879–86

    PubMed  CAS  Article  Google Scholar 

  106. Weng J, Cao Y, Moss N, Zhou M (2006) Modulation of voltage-dependent Shaker family potassium channels by an aldo-keto reductase. J Biol Chem 281:15194–200

    PubMed  CAS  Article  Google Scholar 

  107. Williams CP, Hu N, Shen W, Mashburn AB, Murray KT (2002) Modulation of the human Kv1.5 channel by protein kinase C activation: role of the Kvbeta1.2 subunit. J Pharmacol Exp Ther 302:545–50

    PubMed  CAS  Article  Google Scholar 

  108. Williams MR, Markey JC, Doczi MA, Morielli AD (2007) An essential role for cortactin in the modulation of the potassium channel Kv1.2. Proc Natl Acad Sci U S A 104:17412–7

    PubMed  CAS  Article  Google Scholar 

  109. Yang JW, Vacher H, Park KS, Clark E, Trimmer JS (2007) Trafficking-dependent phosphorylation of Kv1.2 regulates voltage-gated potassium channel cell surface expression. Proc Natl Acad Sci U S A 104:20055–60

    PubMed  CAS  Article  Google Scholar 

  110. Yu FH, Catterall WA (2004) The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE 2004:re15

  111. Yuan LL, Adams JP, Swank M, Sweatt JD, Johnston D (2002) Protein kinase modulation of dendritic K+ channels in hippocampus involves a mitogen-activated protein kinase pathway. J Neurosci 22:4860–8

    PubMed  CAS  Google Scholar 

  112. Zagha E, Ozaita A, Chang SY, Nadal MS, Lin U, Saganich MJ, McCormack T, Akinsanya KO, Qi SY, Rudy B (2005) DPP10 modulates Kv4-mediated A-type potassium channels. J Biol Chem 280:18853–61

    PubMed  CAS  Article  Google Scholar 

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Acknowledgments

Work from our laboratories reviewed here was supported by the Institut National de la Santé et de la Recherche Médicale and Marie Curie 7th framework program grant IRG-2008-239499 (to H. Vacher) and the National Institutes of Health grants NS34383 and NS42225 (to J. S. Trimmer).

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Correspondence to James S. Trimmer.

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Vacher, H., Trimmer, J.S. Diverse roles for auxiliary subunits in phosphorylation-dependent regulation of mammalian brain voltage-gated potassium channels. Pflugers Arch - Eur J Physiol 462, 631 (2011). https://doi.org/10.1007/s00424-011-1004-8

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  • DOI: https://doi.org/10.1007/s00424-011-1004-8

Keywords

  • Hippocampal neurons
  • Potassium channel
  • Regulation
  • Phosphorylation
  • Protein kinase A
  • A-current
  • β subunits
  • Voltage-gated channels