1. ¹Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-Université de Nice, Institut Paul Hamel, Sophia Antipolis, Valbonne, France
2. ²Serono Genetics Institute SA, 5 rue Henri Desbruères, Evry cedex, France

Correspondence: Professor M Lazdunski, Institut de Pharmacologie Moleculaire et Cellulaire, IPMC CNRS UMR 6097, 660 Route des Lucioles, Sophia Antipolis, Valbonn 06560, France. E-mail: lazdunski@ipmc.cnrs.fr

³These authors contributed equally to this work.

Received 10 January 2006; Revised 22 March 2006; Accepted 18 April 2006; Published online 30 May 2006.

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 B-regulatory subunit of the protein phosphatase 2A (PP2A-B). 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 B 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⁺ 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-B subunit significantly increases the current generated by KCNQ2wt, a channel normally inhibited by phosphorylation. The kinase glycogen synthase kinase 3 beta (GSK3) is considered as an interesting target of lithium, the classical drug used in BD. GSK3 phosphorylates the KCNQ2 channel and this phosphorylation is decreased by Li⁺.