| 1 | Psychopharmacology (Berl.) 2008 Jul 199: 47-54 |
|---|---|
| PMID | 18545987 |
| Title | A 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, and KCNQ3/KCNQ5in the Xenopus expression system. We find that wild-type PIP5K2A but not theschizophrenia-associated mutant (N251S)-PIP5K2A activates heteromeric KCNQ2/KCNQ3 and KCNQ3/KCNQ5的分子相关neuronal M channels. Homomeric KCNQ2 andKCNQ5channels 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. 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 | A 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, and KCNQ3/KCNQ5in the Xenopus expression system. We find that wild-type PIP5K2A but not theschizophrenia-associated mutant (N251S)-PIP5K2A activates heteromeric KCNQ2/KCNQ3 and KCNQ3/KCNQ5的分子相关neuronal M channels. Homomeric KCNQ2 andKCNQ5channels 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. 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 |
| 3 | Alcohol. Clin. Exp. Res. 2011 May 35: 963-75 |
| PMID | 21314694 |
| Title | Genomewide association analysis of symptoms of alcohol dependence in the molecular genetics of schizophrenia (MGS2) control sample. |
| Abstract | While genetic influences on alcohol dependence (AD) are substantial, progress in the identification of individual genetic variants that impact on risk has been difficult. We performed a genome-wide association study on 3,169 alcohol consuming subjects from the population-based Molecular Genetics ofschizophrenia(MGS2) control sample. Subjects were asked 7 questions about symptoms of AD which were analyzed by confirmatory factor analysis. Genotyping was performed using the Affymetrix 6.0 array. Three sets of analyses were conducted separately for European American (EA, n = 2,357) and African-American (AA, n = 812) subjects: individual single nucleotide polymorphisms (SNPs), candidate genes and enriched pathways using gene ontology (GO) categories. The symptoms of AD formed a highly coherent single factor. No SNP approached genome-wide significance. In the EA sample, the most significant intragenic SNP was in KCNMA1, the human homolog of the slo-1 gene in C. Elegans. Genes with clusters of significant SNPs included AKAP9, phosphatidylinositol glycan anchor biosynthesis, class G (PIGG), and KCNMA1. In the AA sample, the most significant intragenic SNP was CEACAM6 and genes showing empirically significant SNPs includedKCNQ5, SLC35B4, and MGLL. In the candidate gene based analyses, the most significant findings were with ADH1C, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1) and ankyrin repeat and kinase domain containing 1 (ANKK1) in the EA sample, and ADH5, POMC, and CHRM2 in the AA sample. The ALIGATOR program identified a significant excess of associated SNPs within and near genes in a substantial number of GO categories over a range of statistical stringencies in both the EA and AA sample. While we cannot be highly confident about any single result from these analyses, a number of findings were suggestive and worthy of follow-up. Although quite large samples will be needed to obtain requisite power, the study of AD symptoms in general population samples is a viable complement to case-control studies in identifying genetic risk variants for AD. |
| SCZ Keywords | schizophrenia, schizophrenic |