A gene recently implicated in dopamine intracellular signaling through D2 receptors is AKT1 (v-akt murine thymoma viral oncogene homolog 1). Decreased AKT1 protein levels have been observed in B lymphoblasts in the postmortem prefrontal cortices of patients with schizophrenia furthering the possibility that these findings relate to the pathophysiology of psychosis. Several studies had previously shown association of AKT1 with schizophrenia;however, the risk associated single nucleotide polymorphisms (SNPs) varied across studies. We hypothesized that if dopaminergic signaling is impacted by AKT1, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function, analogous to those observed with the genes described above. We genotyped several SNPs in AKT1 but focused on a coding variation which had been shown to affect protein expression in human B lymphoblasts and sensitivity to radiation induced apoptosis. We confirmed the reported effect on AKT1 protein levels in B lymphoblasts from our normal controls. Other groups in GCAP also found associations with several brain measures related to dopamine function, including cognitive performance linked to frontostriatal circuitry, prefrontal efficiency during executive function assayed with functional magnetic resonance imaging (fMRI), and frontostriatal gray matter volume on MRI. Having preliminary evidence that the diverse cellular effects of COMT may involve additional basic molecular mechanisms, our study of NRG1-induced B lymphoblast migration found effects of COMT val/met genotype on migration and also on phosphorylation of AKT1 (Sei et.al., PloS One, 2010). We studied AKT1 activation in our NRG1-stimulated B lymphoblasts cell system and studied a functional interaction between COMT and AKT1. The analysis of NRG1-induced AKT1 phosphorylation showed reduced phosphorylation in COMT val individuals compared with those carrying the met allele. In this study, we showed a significant interaction of a functional coding polymorphism in AKT1 (rs1130233) and COMT val108/158met genotype on the cellular process of AKT1 activation. The data suggest that AKT1 function is influenced by COMT enzyme activity through competition with phosphatidylserine (PS) synthesis through S-adenosylmethionine (SAM), which regulates AKT1-dependent cellular responses to NRG1-mediated signaling. Because COMT competes with other methylases for the widely used methyl donor, SAM, it may also impact indirectly on DNA methylation. We are working in collaboration with other groups to do targeted gene methylation assays in our lymphocytes. These findings add to the role of COMT in the neurobiology of schizophrenia;the genetic and functional interactions between COMT and AKT1 may provide novel insight into the pathogenesis of schizophrenia.
| Sei, Yoshitatsu; Li, Zhen; Song, Jian et al. (2010) Epistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling in cell models. PLoS One 5:e10789 |
| Tan, Hao-Yang; Nicodemus, Kristin K; Chen, Qiang et al. (2008) Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans. J Clin Invest 118:2200-8 |
