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


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.
Department of Physiology, University of Tuebingen, Gmelinstr. 5, 72076, Tuebingen, Germany.
Olga
O
Fedorenko
Nathalie
N
Strutz-Seebohm
Ulrike
U
Henrion
Oana N
ON
Ureche
Florian
F
Lang
Guiscard
G
Seebohm
Undine E
UE
Lang
D000483:Alleles; D000818:Animals; D004252:DNA Mutational Analysis; D004298:Dopamine / Q000502:physiology; D006801:Humans; D051656:KCNQ Potassium Channels / Q000235:genetics* / Q000502:physiology; D009474:Neurons / Q000502:physiology; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology; D013379:Substrate Specificity; D014982:Xenopus laevis
D051656:KCNQ Potassium Channels; C514871:PIP4K2A protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); D004298:Dopamine