Advertisement

Psychopharmacology

, 199:47 | Cite as

A schizophrenia-linked mutation in PIP5K2A fails to activate neuronal M channels

  • Olga Fedorenko
  • Nathalie Strutz-Seebohm
  • Ulrike Henrion
  • Oana N. Ureche
  • Florian Lang
  • Guiscard SeebohmEmail author
  • Undine E. Lang
Original Investigation

Abstract

Rationale

Evidence for an association between phosphatidylinositol-4-phosphate 5-kinase II alpha (PIP5K2A) and schizophrenia was recently obtained and replicated in several samples. PIP5K2A controls the function of KCNQ channels via phosphatidylinositol-4,5-bisphosphate (PIP2) synthesis. Interestingly, recent data suggest that KCNQ channels suppress basal activity of dopaminergic neurons and dopaminergic firing. Activation of KCNQ accordingly attenuates the central stimulating effects of dopamine, cocaine, methylphenidate, and phenylcyclidine.

Objective

The aim of this study was to explore the functional relevance of PIP5K2A, which might influence schizophrenic behavior.

Materials and methods

Here, we study the effects of the neuronal PIP5K2A on KCNQ2, KCNQ5, KCNQ2/KCNQ3, and KCNQ3/KCNQ5 in the Xenopus expression system.

Results

We find that wild-type PIP5K2A but not the schizophrenia-associated mutant (N251S)-PIP5K2A activates heteromeric KCNQ2/KCNQ3 and KCNQ3/KCNQ5, the molecular correlate of neuronal M channels. Homomeric KCNQ2 and KCNQ5 channels were not activated by the kinase indicating that the presence of KCNQ3 in the channel complex is required for the kinase-mediated effects. Acute application of PI(4,5)P2 and a PIP2 scavenger indicates that the mutation N251S renders the kinase PIP5K2A inactive.

Conclusions

Our results suggest that the schizophrenia-linked mutation of the kinase results in reduced KCNQ channel function and thereby might explain the loss of dopaminergic control in schizophrenic patients. Moreover, the addictive potential of dopaminergic drugs often observed in schizophrenic patients might be explained by this mechanism. At least, the insufficiency of (N251S)-PIP5K2A to stimulate neuronal M channels may contribute to the clinical phenotype of schizophrenia.

Keywords

PIP2 KCNQ Schizophrenia Dopamine Addiction Channel Mutation Potassium Kinase 

Notes

Acknowledgments

The work of Olga Fedorenko was supported by INTAS YS Fellowship (Ref. No. 04-83-3764). We thank Jasmin Bühringer for helping in the preparation of the manuscript.

Conflict of interest statement

The authors declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

References

  1. Anderson RA, Boronenkov IV, Doughman SD, Kunz J, Loijens JC (1999) Phosphatidylinositol phosphate kinases, a multifaceted family of signaling enzymes. J Biol Chem 274:9907–9910PubMedCrossRefGoogle Scholar
  2. Bakker SC, Hoogendoorn ML, Hendriks J, Verzijlbergen K, Caron S, Verduijn W, Selten JP, Pearson PL, Kahn RS, Sinke RJ (2007) The PIP5K2A and RGS4 genes are differentially associated with deficit and non-deficit schizophrenia. Genes Brain Behav 6:113–119PubMedCrossRefGoogle Scholar
  3. Bar KJ, Koschke M, Boettger MK, Berger S, Kabisch A, Sauer H, Voss A, Yeragani VK (2007) Acute psychosis leads to increased QT variability in patients suffering from schizophrenia. Schizophr Res 95:115–123PubMedCrossRefGoogle Scholar
  4. Blackburn-Munro G, Dalby-Brown W, Mirza NR, Mikkelsen JD, Blackburn-Munro RE (2005) Retigabine: chemical synthesis to clinical application. CNS Drug Rev 11:1–20PubMedGoogle Scholar
  5. Brown DA, Hughes SA, Marsh SJ, Tinker A (2007) Regulation of M(Kv7.2/7.3) channels in neurons by PIP2 and products of PIP2 hydrolysis: significance for receptor-mediated inhibition. J Physiol 582:917–925PubMedCrossRefGoogle Scholar
  6. Bubser M, Deutch AY (2002) Differential effects of typical and atypical antipsychotic drugs on striosome and matrix compartments of the striatum. Eur J Neurosci 15:713–720PubMedCrossRefGoogle Scholar
  7. Dalby-Brown W, Hansen HH, Korsgaard MP, Mirza N, Olesen SP (2006) K(v)7 channels: function, pharmacology and channel modulators. Curr Top Med Chem 6:999–1023PubMedCrossRefGoogle Scholar
  8. Delmas P, Brown DA (2005) Pathways modulating neural KCNQ/M (Kv7) potassium channels. Nat Rev Neurosci 6:850–862PubMedCrossRefGoogle Scholar
  9. Doughman RL, Firestone AJ, Wojtasiak ML, Bunce MW, Anderson RA (2003) Membrane ruffling requires coordination between type I phosphatidylinositol phosphate kinase and Rac signaling. J Biol Chem 278:M211397200CrossRefGoogle Scholar
  10. Guex N, Peitsch MC (1997) SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18:2714–2723PubMedCrossRefGoogle Scholar
  11. Guillin O, Abi-Dargham A, Laruelle M (2007) Neurobiology of dopamine in schizophrenia. Int Rev Neurobiol 78:1–39PubMedCrossRefGoogle Scholar
  12. Gupta PD, Johar K, Vasavada A (2004) Causative and preventive action of calcium in cataracto-genesis. Acta Pharmacol Sin 25:1250–1256PubMedGoogle Scholar
  13. Hansen HH, Ebbesen C, Mathiesen C, Weikop P, Ronn LC, Waroux O, Scuvée-Moreau J, Seutin V, Mikkelsen JD (2006) The KCNQ channel opener retigabine inhibits the activity of mesencephalic dopaminergic systems of the rat. J Pharmacol Exp Ther 318:1006–1019PubMedCrossRefGoogle Scholar
  14. Hansen HH, Andreasen JT, Weikop P, Mirza N, Scheel-Krüger J, Mikkelsen JD (2007) The neuronal KCNQ channel opener retigabine inhibits locomotor activity and reduces forebrain excitatory responses to the psychostimulants cocaine, methylphenidate and phencyclidine. Eur J Pharmacol 570:77–88PubMedCrossRefGoogle Scholar
  15. He Z, Li Z, Shi Y, Tang W, Huang K, Ma G, Zhou J, Meng J, Li H, Feng G, He L (2007) The PIP5K2A gene and schizophrenia in the Chinese population—a case–control study. Schizophr Res 94:359–365PubMedCrossRefGoogle Scholar
  16. Hu H, Vervaeke K, Storm JF (2007) M-channels (Kv7/KCNQ channels) that regulate synaptic integration, excitability, and spike pattern of CA1 pyramidal cells are located in the perisomatic region. J Neurosci 27:1853–1867PubMedCrossRefGoogle Scholar
  17. Jentsch TJ, Schroeder BC, Kubisch C, Friedrich T, Stein V (2000) Pathophysiology of KCNQ channels: neonatal epilepsy and progressive deafness. Epilepsia 41:1068–1069PubMedCrossRefGoogle Scholar
  18. Korsgaard MP, Hartz BP, Brown WD, Ahring PK, Strobaek D, Mirza NR (2005) Anxiolytic effects of Maxipost (BMS-204352) and retigabine via activation of neuronal Kv7 channels. J Pharmacol Exp Ther 314:282–292PubMedCrossRefGoogle Scholar
  19. Koyama S, Appel SB (2006) Characterization of M-current in ventral tegmental area dopamine neurons. J Neurophysiol 96:535–543PubMedCrossRefGoogle Scholar
  20. Lang F, Klingel K, Wagner CA, Stegen C, Warntges S, Friedrich B, Lanzendorfer M, Melzig J, Moschen I, Steuer S, Waldegger S, Sauter M, Paulmichl M, Gerke V, Risler T, Gamba G, Capasso G, Kandolf R, Hebert SC, Massry SG, Broër S (2000) Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy. Proc Natl Acad Sci U S A 97:8157–8162PubMedCrossRefGoogle Scholar
  21. Lang UE, Puls I, Muller DJ, Strutz-Seebohm N, Gallinat J (2007) Molecular mechanisms of schizophrenia. Cell Physiol Biochem 20:687–702PubMedCrossRefGoogle Scholar
  22. Lerche H, Weber YG, Jurkat-Rott K, Lehmann-Horn F (2005) Ion channel defects in idiopathic epilepsies. Curr Pharm Des 11:2737–2752PubMedCrossRefGoogle Scholar
  23. Li Y, Gamper N, Hilgemann DW, Shapiro MS (2005) Regulation of Kv7 (KCNQ) K+ channel open probability by phosphatidylinositol 4,5-bisphosphate. J Neurosci 25:9825–9835PubMedCrossRefGoogle Scholar
  24. Lieberman JA, Kane JM, Sarantakos S, Gadaleta D, Woerner M, Alvir J, Ramos-Lorenzi J (1987) Prediction of relapse in schizophrenia. Arch Gen Psychiatry 44:597–603PubMedGoogle Scholar
  25. Lieberman JA, Kane JM, Johns CA (1989) Clozapine: guidelines for clinical management. J Clin Psychiatry 50:329–338PubMedGoogle Scholar
  26. Marquez MF, Ramos-Kuri M, Hernandez-Pacheco G, Estrada J, Fabregat JR, Perez-Vielma N, Gómez-Flores J, González-Hermosillo A, Cárdenas M, Vargas-Alarcón G (2006) (KCNQ 1 (KvLQT1) missense mutation causing congenital long QT syndrome (Jervell–Lange–Nielsen) in a Mexican family). Arch Cardiol Mex 76:257–262PubMedGoogle Scholar
  27. Martire M, D'Amico M, Panza E, Miceli F, Viggiano D, Lavergata F, Iannotti FA, Barrese V, Preziosi P, Annunziato L, Taglialatela M (2007) Involvement of KCNQ2 subunits in (3H)dopamine release triggered by depolarization and pre-synaptic muscarinic receptor activation from rat striatal synaptosomes. J Neurochem 102:179–193PubMedCrossRefGoogle Scholar
  28. McLaughlin S, Wang J, Gambhir A, Murray D (2002) PI4,5P(2) and proteins: interactions, organization, and information flow. Annu Rev Biophys Biomol Struct 31:151–175PubMedCrossRefGoogle Scholar
  29. Mikkelsen JD (2004) The KCNQ channel activator retigabine blocks haloperidol-induced c-Fos expression in the striatum of the rat. Neurosci Lett 362:240–243PubMedCrossRefGoogle Scholar
  30. Piccinin S, Randall AD, Brown JT (2006) KCNQ/Kv7 channel regulation of hippocampal gamma-frequency firing in the absence of synaptic transmission. J Neurophysiol 95:3105–3112PubMedCrossRefGoogle Scholar
  31. Rameh LE, Tolias KF, Duckworth BC, Cantley LC (1997) A new pathway for synthesis of phosphatidylinositol-4,5 bisphosphate. Nature 390:192–196PubMedCrossRefGoogle Scholar
  32. Rohacs T, Chen J, Prestwich GD, Logothetis DE (1999) Distinct specificities of inwardly rectifying K(+) channels for phosphoinositides. J Biol Chem 274:36065–36072PubMedCrossRefGoogle Scholar
  33. Schmidt WJ, Schuster G, Wacker E, Pergande G (1997) Antiparkinsonian and other motor effects of flupirtine alone and in combination with dopaminergic drugs. Eur J Pharmacol 327:1–9PubMedCrossRefGoogle Scholar
  34. Schwab SG, Knapp M, Sklar P, Eckstein GN, Sewekow C, Borrmann-Hassenbach M, Albus M, Becker T, Hallmayer JF, Lerer B, Maier W, Wildenauer DB (2006) Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIalpha gene (PIP5K2A) with schizophrenia. Mol Psychiatry 11:837–846PubMedCrossRefGoogle Scholar
  35. Shyng SL, Barbieri A, Gumusboga A, Cukras C, Pike L, Stahl PD, Nichols CG (2000) Modulation of nucleotide sensitivity of ATP-sensitive potassium channels by phosphatidylinositol-4-phosphate 5-kinase. Proc Natl Acad Sci U S A 97:937–941PubMedCrossRefGoogle Scholar
  36. Stone JM, Pilowsky LS (2007) Novel targets for drugs in schizophrenia. CNS Neurol Disord Drug Targets 6:265–272PubMedCrossRefGoogle Scholar
  37. Stopkova P, Saito T, Fann CS, Papolos DF, Vevera J, Zukov I, Stryjer R, Strous RD, Lachman HM (2003) Polymorphism screening of PIP5K2A: a candidate gene for chromosome 10p-linked psychiatric disorders. Am J Med Genet B Neuropsychiatr Genet 123:50–58CrossRefGoogle Scholar
  38. Stopkova P, Vevera J, Paclt I, Zukov I, Papolos DF, Saito T, Lachman HM (2005) Screening of PIP5K2A promoter region for mutations in bipolar disorder and schizophrenia. Psychiatr Genet 15:223–227PubMedCrossRefGoogle Scholar
  39. Suh BC, Inoue T, Meyer T, Hille B (2006) Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels. Science 314:1454–1457PubMedCrossRefGoogle Scholar
  40. Thirthalli J, Benegal V (2006) Psychosis among substance users. Curr Opin Psychiatry 19:239–245PubMedCrossRefGoogle Scholar
  41. Vervaeke K, Gu N, Agdestein C, Hu H, Storm JF (2006) Kv7/KCNQ/M-channels in rat glutamatergic hippocampal axons and their role in regulation of excitability and transmitter release. J Physiol 576:235–256PubMedCrossRefGoogle Scholar
  42. Wagner CA, Friedrich B, Setiawan I, Lang F, Broer S (2000) The use of Xenopus laevis oocytes for the functional characterization of heterologously expressed membrane proteins. Cell Physiol Biochem 10:1–12PubMedCrossRefGoogle Scholar
  43. Zhang H, Craciun LC, Mirshahi T, Rohacs T, Lopes CM, Jin T, Logothetis DE (2003) PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron 37:963–975PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Olga Fedorenko
    • 1
    • 2
  • Nathalie Strutz-Seebohm
    • 1
    • 4
  • Ulrike Henrion
    • 1
    • 4
  • Oana N. Ureche
    • 1
  • Florian Lang
    • 1
  • Guiscard Seebohm
    • 1
    • 4
    Email author
  • Undine E. Lang
    • 3
  1. 1.Department of PhysiologyUniversity of TuebingenTuebingenGermany
  2. 2.Mental Health Research InstituteTomskRussia
  3. 3.Department of Psychiatry and PsychotherapyCharité Campus MitteBerlinGermany
  4. 4.Lehrstuhl für Biochemie I - RezeptorbiochemieRuhr-University BochumBochumGermany

Personalised recommendations