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A schizophrenia-linked mutation in PIP5K2A fails to activate neuronal M channels.
Fedorenko O
,
Strutz-Seebohm N
,
Henrion U
,
Ureche ON
,
Lang F
,
Seebohm G
,
Lang UE
.
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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.
Anderson,
Phosphatidylinositol phosphate kinases, a multifaceted family of signaling enzymes.
1999, Pubmed
Anderson,
Phosphatidylinositol phosphate kinases, a multifaceted family of signaling enzymes.
1999,
Pubmed
Bakker,
The PIP5K2A and RGS4 genes are differentially associated with deficit and non-deficit schizophrenia.
2007,
Pubmed
Bär,
Acute psychosis leads to increased QT variability in patients suffering from schizophrenia.
2007,
Pubmed
Blackburn-Munro,
Retigabine: chemical synthesis to clinical application.
2005,
Pubmed
Brown,
Regulation of M(Kv7.2/7.3) channels in neurons by PIP(2) and products of PIP(2) hydrolysis: significance for receptor-mediated inhibition.
2007,
Pubmed
Bubser,
Differential effects of typical and atypical antipsychotic drugs on striosome and matrix compartments of the striatum.
2002,
Pubmed
Dalby-Brown,
K(v)7 channels: function, pharmacology and channel modulators.
2006,
Pubmed
Delmas,
Pathways modulating neural KCNQ/M (Kv7) potassium channels.
2005,
Pubmed
Doughman,
Membrane ruffling requires coordination between type Ialpha phosphatidylinositol phosphate kinase and Rac signaling.
2003,
Pubmed
Guex,
SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling.
1997,
Pubmed
Guillin,
Neurobiology of dopamine in schizophrenia.
2007,
Pubmed
Gupta,
Causative and preventive action of calcium in cataracto-genesis.
2004,
Pubmed
Hansen,
The neuronal KCNQ channel opener retigabine inhibits locomotor activity and reduces forebrain excitatory responses to the psychostimulants cocaine, methylphenidate and phencyclidine.
2007,
Pubmed
Hansen,
The KCNQ channel opener retigabine inhibits the activity of mesencephalic dopaminergic systems of the rat.
2006,
Pubmed
He,
The PIP5K2A gene and schizophrenia in the Chinese population--a case-control study.
2007,
Pubmed
Hu,
M-channels (Kv7/KCNQ channels) that regulate synaptic integration, excitability, and spike pattern of CA1 pyramidal cells are located in the perisomatic region.
2007,
Pubmed
Jentsch,
Pathophysiology of KCNQ channels: neonatal epilepsy and progressive deafness.
2000,
Pubmed
Korsgaard,
Anxiolytic effects of Maxipost (BMS-204352) and retigabine via activation of neuronal Kv7 channels.
2005,
Pubmed
,
Xenbase
Koyama,
Characterization of M-current in ventral tegmental area dopamine neurons.
2006,
Pubmed
Lang,
Molecular mechanisms of schizophrenia.
2007,
Pubmed
Lang,
Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy.
2000,
Pubmed
,
Xenbase
Lerche,
Ion channel defects in idiopathic epilepsies.
2005,
Pubmed
Li,
Regulation of Kv7 (KCNQ) K+ channel open probability by phosphatidylinositol 4,5-bisphosphate.
2005,
Pubmed
Lieberman,
Prediction of relapse in schizophrenia.
1987,
Pubmed
Lieberman,
Clozapine: guidelines for clinical management.
1989,
Pubmed
Márquez,
[KCNQ 1 (KvLQT1) missense mutation causing congenital long QT syndrome (Jervell-Lange-Nielsen) in a Mexican family].
2006,
Pubmed
Martire,
Involvement of KCNQ2 subunits in [3H]dopamine release triggered by depolarization and pre-synaptic muscarinic receptor activation from rat striatal synaptosomes.
2007,
Pubmed
McLaughlin,
PIP(2) and proteins: interactions, organization, and information flow.
2002,
Pubmed
Mikkelsen,
The KCNQ channel activator retigabine blocks haloperidol-induced c-Fos expression in the striatum of the rat.
2004,
Pubmed
Piccinin,
KCNQ/Kv7 channel regulation of hippocampal gamma-frequency firing in the absence of synaptic transmission.
2006,
Pubmed
Rameh,
A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate.
1997,
Pubmed
Rohács,
Distinct specificities of inwardly rectifying K(+) channels for phosphoinositides.
1999,
Pubmed
,
Xenbase
Schmidt,
Antiparkinsonian and other motor effects of flupirtine alone and in combination with dopaminergic drugs.
1997,
Pubmed
Schwab,
Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIalpha gene (PIP5K2A) with schizophrenia.
2006,
Pubmed
Shyng,
Modulation of nucleotide sensitivity of ATP-sensitive potassium channels by phosphatidylinositol-4-phosphate 5-kinase.
2000,
Pubmed
Stone,
Novel targets for drugs in schizophrenia.
2007,
Pubmed
Stopkova,
Screening of PIP5K2A promoter region for mutations in bipolar disorder and schizophrenia.
2005,
Pubmed
Stopkova,
Polymorphism screening of PIP5K2A: a candidate gene for chromosome 10p-linked psychiatric disorders.
2003,
Pubmed
Suh,
Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels.
2006,
Pubmed
Thirthalli,
Psychosis among substance users.
2006,
Pubmed
Vervaeke,
Kv7/KCNQ/M-channels in rat glutamatergic hippocampal axons and their role in regulation of excitability and transmitter release.
2006,
Pubmed
Wagner,
The use of Xenopus laevis oocytes for the functional characterization of heterologously expressed membrane proteins.
2000,
Pubmed
,
Xenbase
Zhang,
PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents.
2003,
Pubmed
,
Xenbase
