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Originally published In Press as doi:10.1074/jbc.M606092200 on July 24, 2006

J. Biol. Chem., Vol. 281, Issue 39, 28910-28918, September 29, 2006
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Membrane Potential-regulated Transcription of the Resting K+ Conductance TASK-3 via the Calcineurin Pathway*Formula

Marc Zanzouri1, Inger Lauritzen1, Fabrice Duprat, Michel Mazzuca, Florian Lesage, Michel Lazdunski, and Amanda Patel2

From the Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR 6097, Université de Nice-Sophia Antipolis, Valbonne 06560, France

The 2P domain K+ channel TASK-3 is highly expressed in cerebellar granule neurons where it has been proposed to underlie the K+ leak conductance, IKso. In a previous work we showed that expression of TASK-3 increases in cerebellar granule neurons as they mature in culture. Here we show that within the cerebellum, levels of TASK-3 mRNA increase as granule neurons migrate to their adult positions and receive excitatory mossy fiber input. To understand the mechanism of this increase in TASK-3 expression we used an in vitro model culturing the neurons in either depolarizing conditions mimicking neuronal activity (25K, 25 mM KCl) or in conditions which approach deafferentation (5K, 5 mM KCl). An important increase in TASK-3 mRNA is uniquely observed in 25K and is specific since other background K+ channel levels remain unchanged or decrease. The rise in TASK-3 mRNA leads to an increase in TASK-3 protein and the IKso conductance resulting in hyperpolarization. Blocking L-type calcium channels or their downstream effector calcineurin, abrogates TASK-3 expression and IKso, leading to hyperexcitability. This is the first study demonstrating that depolarization-induced Ca2+ entry can directly regulate cellular excitability by dynamically regulating the transcription of a resting K+ conductance. The appearance of this conductance may play an important role in the transition of depolarized immature neurons to their mature hyperpolarized state during neuronal development.


Received for publication, June 26, 2006 , and in revised form, July 24, 2006.

* This work was funded by La Ligue Nationale contre le Cancer (Equipe labelisé) and Association Pour La Recherche Sur le Cancer (Subvention number 3331) and the Institute Paul Hamel and by the CNRS. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Formula The on-line version of this article (available at http://www.jbc.org) contains supplemental primer information and Fig.1.

1 These authors contributed equally to this work.

2 To whom correspondence should be addressed: IPMC-CNRS, UMR6097, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France. Tel.: 33-493957730; Fax: 33-493957704; E-mail: patel{at}ipmc.cnrs.fr.


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