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1 Department of Physiology, University of Freiburg, Hermann-Herder-Strasse 7, 79104 Freiburg, Germany
The defining characteristic of large-conductance Ca2+- and voltage-activated K+ channels (BKCa) is their allosteric activation by two distinct stimuli, membrane depolarization and cytosolic Ca2+ ions. In this allosteric gating, increasing cytosolic Ca2+ concentration ([Ca2+]i) shifts the depolarization required for channel opening into the physiological voltage range. In fact, according to present knowledge, elevation of [Ca2+]i to micromolar levels is the only means to activate BKCa at membrane potentials below 0 mV. We recorded BKCa-mediated currents from auditory inner hair cells (IHCs) in acutely isolated organs of Corti using the patch-clamp technique in whole-cell and excised patch configuration. In inside-out and outside-out patches, activation of BKCa channels from IHCs showed the prototypic sensitivity to increased [Ca2+]i. However, channel activation at 0 [Ca2+]i occurred at unusually negative potentials (half-maximal activation (Vh) around 0 mV), indicating that a large fraction of the channels can be activated at physiological voltages without elevated [Ca2+]i. In intact IHCs, the activation curve of BKCa currents recorded in whole-cell configuration exhibited a Vh of –42 mV together with a high voltage dependence (slope factor of 10 mV) and submillisecond onset of current. Surprisingly, this activation was independent of changes in local [Ca2+]i as shown by experiments that interfered with Ca2+ influx through voltage-gated Ca2+ (Cav) channels, release of Ca2+ from internal stores, or intracellular buffer capacity. This behaviour is not due to ß-subunits of BKCa (BKß), as genetic inactivation of the ß-subunit expressed in IHCs, KCNMB1, did not affect BKCa gating. We conclude that the BKCa channel protein in IHCs may be modified in order to rapidly activate and deactivate at resting [Ca2+]i. Our results suggest that BKCa may function as a purely voltage-gated K+ channel with exceptionally rapid activation kinetics, challenging the view that both increased cytosolic Ca2+ and depolarization are generally required for activation of BKCa.
(Received 14 July 2005;
accepted after revision 2 September 2005;
first published online 8 September 2005)
Corresponding author D. Oliver: Physiologisches Institut, Universität Freiburg, Hermann-Herder-Strasse 7, 79104 Freiburg, Germany. Email: dominik.oliver{at}physiologie.uni-freiburg.de
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