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

The Pharmacogenomics Journal volume 7, pages 123–132 (2007)Cite this article

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 Bγ-regulatory subunit of the protein phosphatase 2A (PP2A-Bγ). 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 Bγ 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-Bγ subunit significantly increases the current generated by KCNQ2wt, a channel normally inhibited by phosphorylation. The kinase glycogen synthase kinase 3 beta (GSK3β) is considered as an interesting target of lithium, the classical drug used in BD. GSK3β phosphorylates the KCNQ2 channel and this phosphorylation is decreased by Li+.

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Acknowledgements

We are very grateful to Dr Thomas Jentsch for the generous gift of the KCNQ2wt channels and Dr Gary Buell for helpful discussion. We thank Martine Jodar, Nathalie Leroudier, Aurélie Kiers and Franck Aguila for their expert technical assistance, Linda Belo for reading the manuscript and Yvette Benhamou for secretarial assistance.

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  1. M Borsotto and L Cavarec: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-Université de Nice, Institut Paul Hamel, Sophia Antipolis, Valbonne, France

    M Borsotto, G Romey & M Lazdunski

  2. Serono Genetics Institute SA, 5 rue Henri Desbruères, Evry cedex, France

    L Cavarec, M Bouillot, F Macciardi, A Delaye, M Nasroune, M Bastucci, J-L Sambucy, J-J Luan, A Charpagne, V Jouët, R Léger, D Cohen & I Chumakov

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Correspondence to M Lazdunski.

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Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website (http://www.nature.com/tpj)

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Borsotto, M., Cavarec, L., Bouillot, M. et al. PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder. Pharmacogenomics J 7, 123–132 (2007). https://doi.org/10.1038/sj.tpj.6500400

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