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The Journal of Neuroscience, August 20, 2008, 28(34):8545-8552; doi:10.1523/JNEUROSCI.1962-08.2008

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Cellular/Molecular
Mtap2 Is a Constituent of the Protein Network That Regulates Twik-Related K+ Channel Expression and Trafficking

Guillaume Sandoz, Magalie P. Tardy, Susanne Thümmler, Sylvain Feliciangeli, Michel Lazdunski, and Florian Lesage

Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6097, Institut Paul Hamel, 06560 Valbonne Sophia-Antipolis, France, and Université de Nice Sophia-Antipolis, Faculté des Sciences, 06000 Nice, France

Correspondence should be addressed to Florian Lesage, Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, 660 route des Lucioles, 06560 Valbonne Sophia-Antipolis, France. Email: lesage{at}ipmc.cnrs.fr

Twik-related K+ (TREK) channels produce background currents that regulate cell excitability. In vivo, TREK-1 is involved in neuronal processes including neuroprotection against ischemia, general anesthesia, pain perception, and mood. Recently, we demonstrated that A-kinase anchoring protein AKAP150 binds to a major regulatory domain of TREK-1, promoting drastic changes in channel regulation by polyunsaturated fatty acids, pH, and stretch, and by G-protein-coupled receptors to neurotransmitters and hormones. Here, we show that the microtubule-associated protein Mtap2 is another constituent of native TREK channels in the brain. Mtap2 binding to TREK-1 and TREK-2 does not affect directly channel properties but enhances channel surface expression and current density. This effect relies on Mtap2 binding to microtubules. Mtap2 and AKAP150 interacting sites in TREK-1 are distinct and both proteins can dock simultaneously. Their effects on TREK-1 surface expression and activation are cumulative. In neurons, the three proteins are simultaneously detected in postsynaptic dense bodies. AKAP150 and Mtap2 put TREK channels at the center of a complex protein network that finely tunes channel trafficking, addressing, and regulation.

Key words: potassium channels; proteomics; microtubules; trafficking; postsynaptic dense bodies; scaffolding

Received Feb. 7, 2008; revised July 10, 2008; accepted July 12, 2008.

Correspondence should be addressed to Florian Lesage, Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, 660 route des Lucioles, 06560 Valbonne Sophia-Antipolis, France. Email: lesage{at}ipmc.cnrs.fr




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