PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder

Abstract

Many bipolar affective disorder (BD) susceptibility loci have been identified but the molecular mechanisms responsible for the disease remain to be elucidated. In the locus 4p16, several candidate genes were identified but none of them was definitively shown to be associated with BD. In this region, the PPP2R2C gene encodes the Bg-regulatory subunit of the protein phosphatase 2A (PP2A-Bg). First, we identified, in two different populations, single nucleotide polymorphisms and risk haplotypes for this gene that are associated to BD. Then, we used the Bg subunit as bait to screen a human brain cDNA library with the yeast two-hybrid technique. This led us to two new splice variants of KCNQ2 channels and to the KCNQ2 channel itself. This unusual K þ channel has particularly interesting functional properties and belongs to a channel family that is already known to be implicated in several other monogenic diseases. In one of the BD populations, we also found a genetic association between the KCNQ2 gene and BD. We show that KCNQ2 splice variants differ from native channels by their shortened C-terminal sequences and are unique as they are active and exert a dominant-negative effect on KCNQ2 wild-type (wt) channel activity. We also show that the PP2A-Bg subunit significantly increases the current generated by KCNQ2wt, a channel normally inhibited by phosphorylation. The kinase glycogen synthase kinase 3 beta (GSK3b) is considered as an interesting target of lithium, the classical drug used in BD. GSK3b phosphorylates the KCNQ2 channel and this phosphorylation is decreased by Li þ .

Integrative genome-wide association analysis of cytoarchitectural abnormalities in the prefrontal cortex of psychiatric disorders

“…35 However, there was no significant association between the cis SNPs and the expression level of the gene in the SNPExpress database, 24 and we were unable to confirm the SNP association in our samples, as the gene is absent from our expression microarray data set. Nevertheless, deficits in oligodendrocytes have been identified as a significant neuropathology in schizophrenia and in bipolar disorder, 36,37 and genome-wide expression profiling revealed that oligodendrocyte-related genes are downregulated in the PFC of both schizophrenia and bipolar disorder.…”

Protein Phosphatase 2A and Glycogen Synthase Kinase 3 Signaling Modulate Prepulse Inhibition of the Acoustic Startle Response by Altering Cortical M-Type Potassium Channel Activity

“…Recently, the M-type potassium channel subunit gene, Kcnq2, has been identified as a putative GSK3␤ substrate (Borsotto et al, 2007). Loss-of function mutations in Kcnq2 result in a mild form of epilepsy Singh et al, 1998;Cooper et al, 2000;Mulley et al, 2003) and a mutation in the phosphatidylinositol 4-phosphate 5-kinase II␣ (PIP5K2A) gene, which leads to reduced M-channel activity, has been linked to schizophrenia (Fedorenko et al, 2008).…”

Lithium improved behavioral and epileptic symptoms in an adolescent with ring chromosome 20 and bipolar disorder not otherwise specified

“…Additionally, several cases have been reported with typical epileptic manifestations of R(20) syndrome without KCNQ2 deletion, probably due to a dysregulation of its expression or telomeric instability leading to interstitial deletion 2122 or PPP2R2C 23…”

“…Unfortunately, ezogabine has been removed from prescription after a warning from the Food and Drug Administration due to retinal pigmentary changes and blue skin discoloration with chronic use 28. Interestingly, ezogabine and lithium share similar final pathways and could both trigger the opening of potassium voltage‐gated channels 23, 27. By maintaining the KCNQ2 channel open, they may reduce the excitability of the postsynaptic neuron.…”

“…By maintaining the KCNQ2 channel open, they may reduce the excitability of the postsynaptic neuron. In 2007, Borsotto et al23 extensively described how lithium might impact KCNQ2 by two mechanisms (Figure 3). First, lithium inhibits GSK3β, an enzyme that is involved in the phosphorylation of KCNQ2 .…”