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Tuning Magnesium Sensitivity of BK Channels by Mutations

Department of Biomedical Engineering and Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, Missouri 63130

Correspondence: Address reprint requests to Jianmin Cui, Dept. of Biomedical Engineering, Washington University, St. Louis, MO 63130. Tel.: 314-935-8896; Fax: 314-935-7448; E-mail: jcui{at}biomed.wustl.edu.

Intracellular Mg²⁺ at physiological concentrations activates mSlo1 BK channels by binding to a metal-binding site in the cytosolic domain. Previous studies suggest that residues E374, Q397, and E399 are important in Mg²⁺ binding. In the present study, we show that mutations of E374 or E399 to other amino acids, except for Asp, abolish Mg²⁺ sensitivity. These results further support that the side chains of E374 and E399 are essential for Mg²⁺ coordination. To the contrary, none of the Q397 mutations abolishes Mg²⁺ sensitivity, suggesting that its side chain may not coordinate to Mg²⁺. However, because Q397 is spatially close to E374 and E399, its mutations affect the Mg²⁺ sensitivity of channel gating by either reducing or increasing the Mg²⁺ binding affinity. The pattern of mutational effects and the effect of chemical modification of Q397C indicate that Q397 is involved in the Mg²⁺-dependent activation of BK channels and that mutations of Q397 alter Mg²⁺ sensitivity by affecting the conformation of the Mg²⁺ binding site as well as by electrostatic interactions with the bound Mg²⁺ ion.

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