| 1 | Psychopharmacology (Berl.) 2008 Jul 199: 47-54 |
|---|---|
| PMID | 18545987 |
| Title | 一个schizophrenia-linked mutation in PIP5K2A fails to activate neuronal M channels. |
| Abstract | Evidence for an association between phosphatidylinositol-4-phosphate 5-kinase II alpha (PIP5K2A) andschizophreniawas 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. The aim of this study was to explore the functional relevance of PIP5K2A, which might influenceschizophrenicbehavior. Here, we study the effects of the neuronal PIP5K2A on KCNQ2, KCNQ5, KCNQ2/KCNQ3, andKCNQ3/KCNQ5 in the Xenopus expression system. We find that wild-type PIP5K2A but not theschizophrenia-associated mutant (N251S)-PIP5K2A activates heteromeric KCNQ2/KCNQ3andKCNQ3/KCNQ5, the molecular correlate of neuronal M channels. Homomeric KCNQ2 and KCNQ5 channels were not activated by the kinase indicating that the presence ofKCNQ3in 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. Our results suggest that theschizophrenia-linked mutation of the kinase results in reduced KCNQ channel function and thereby might explain the loss of dopaminergic control inschizophrenicpatients. Moreover, the addictive potential of dopaminergic drugs often observed inschizophrenicpatients might be explained by this mechanism. At least, the insufficiency of (N251S)-PIP5K2A to stimulate neuronal M channels may contribute to the clinical phenotype ofschizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Psychopharmacology (Berl.) 2008 Jul 199: 47-54 |
| PMID | 18545987 |
| Title | 一个schizophrenia-linked mutation in PIP5K2A fails to activate neuronal M channels. |
| Abstract | Evidence for an association between phosphatidylinositol-4-phosphate 5-kinase II alpha (PIP5K2A) andschizophreniawas 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. The aim of this study was to explore the functional relevance of PIP5K2A, which might influenceschizophrenicbehavior. Here, we study the effects of the neuronal PIP5K2A on KCNQ2, KCNQ5, KCNQ2/KCNQ3, andKCNQ3/KCNQ5 in the Xenopus expression system. We find that wild-type PIP5K2A but not theschizophrenia-associated mutant (N251S)-PIP5K2A activates heteromeric KCNQ2/KCNQ3andKCNQ3/KCNQ5, the molecular correlate of neuronal M channels. Homomeric KCNQ2 and KCNQ5 channels were not activated by the kinase indicating that the presence ofKCNQ3in 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. Our results suggest that theschizophrenia-linked mutation of the kinase results in reduced KCNQ channel function and thereby might explain the loss of dopaminergic control inschizophrenicpatients. Moreover, the addictive potential of dopaminergic drugs often observed inschizophrenicpatients might be explained by this mechanism. At least, the insufficiency of (N251S)-PIP5K2A to stimulate neuronal M channels may contribute to the clinical phenotype ofschizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |