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Science 314 (5799): 615-620

Copyright © 2006 by the American Association for the Advancement of Science

BKCa-Cav Channel Complexes Mediate Rapid and Localized Ca2+-Activated K+ Signaling

Henrike Berkefeld,1* Claudia A. Sailer,1,3* Wolfgang Bildl,1,2 Volker Rohde,2 Jörg-Oliver Thumfart,1 Silke Eble,1 Norbert Klugbauer,4 Ellen Reisinger,1 Josef Bischofberger,1 Dominik Oliver,1 Hans-Günther Knaus,3 Uwe Schulte,2{dagger} Bernd Fakler1{dagger}

Abstract: Large-conductance calcium- and voltage-activated potassium channels (BKCa) are dually activated by membrane depolarization and elevation of cytosolic calcium ions (Ca2+). Under normal cellular conditions, BKCa channel activation requires Ca2+ concentrations that typically occur in close proximity to Ca2+ sources. We show that BKCa channels affinity-purified from rat brain are assembled into macromolecular complexes with the voltage-gated calcium channels Cav1.2 (L-type), Cav2.1 (P/Q-type), and Cav2.2 (N-type). Heterologously expressed BKCa-Cav complexes reconstitute a functional "Ca2+ nanodomain" where Ca2+ influx through the Cav channel activates BKCa in the physiological voltage range with submillisecond kinetics. Complex formation with distinct Cav channels enables BKCa-mediated membrane hyperpolarization that controls neuronal firing pattern and release of hormones and transmitters in the central nervous system.

1 Institute of Physiology, University of Freiburg, Hermann-Herder-Strasse 7, 79104 Freiburg, Germany.
2 Logopharm GmbH, Hermann-Herder-Strasse 7, 79104 Freiburg, Germany.
3 Division of Molecular and Cellular Pharmacology, Medical University Innsbruck, Peter-Mayr-Strasse 1, A-6020 Innsbruck, Austria.
4 Institute of Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25,79104 Freiburg, Germany.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. Email: bernd.fakler{at} (B.F.); u.schulte{at} (U.S.)

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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