Subunit-specific Effect of the Voltage Sensor Domain on Ca²⁺ Sensitivity of BK Channels

¹ Washington University

^* To whom correspondence should be addressed. E-mail: jcui{at}biomed.wustl.edu.

Submitted on September 7, 2007
Revised on October 4, 2007
Accepted on 21 February 2008

	Abstract

Large conductance, Ca²⁺- and voltage-activated K⁺ (BK) channels, composed of pore-forming subunits and auxiliary subunits, play important roles in diverse physiological processes. The differences in BK channel phenotypes are primarily due to the tissue-specific expression of subunits (1-4) that modulate channel function differently. Yet, the molecular basis of the subunit-specific regulation is not clear. Here we report that the perturbation of voltage sensor in BK channels by mutations selectively disrupts the ability of the 1 subunit, but not that of the 2 subunit, to enhance apparent Ca²⁺ sensitivity. These mutations change the number of equivalent gating charges, the voltage dependence of voltage sensor movements, the open-close equilibrium of the channel and the allosteric coupling between voltage sensor movements and channel opening to various degrees, indicating that they alter the conformation and movements of the voltage sensor and the activation gate. Similarly, the ability of the 1 subunit to enhance apparent Ca²⁺ sensitivity is diminished to various degrees, correlating quantitatively with the shift of voltage dependence of voltage sensor movements. In contrast, none of these mutations significantly reduce the ability of the 2 subunit to enhance Ca²⁺ sensitivity. These results suggest that the 1 subunit enhances Ca²⁺ sensitivity by altering the conformation and movements of the voltage sensor, while the similar function of the 2 subunit is governed by a distinct mechanism.

Key Words: BK channels, Beta subunits, Calcium sensitivity, Voltage sensor domain