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The Journal of Neuroscience, July 1, 1999, 19(13):5255-5264

Molecular Basis for the Inactivation of Ca²⁺- and Voltage-Dependent BK Channels in Adrenal Chromaffin Cells and Rat Insulinoma Tumor Cells

Xiao-Ming Xia ¹, Jiu Ping Ding ¹, and Christopher J. Lingle ^{1, 2}

Departments of ¹ Anesthesiology and ² Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110

Large-conductance Ca²⁺- and voltage-dependent potassium (BK) channels exhibit functional diversity not explained by known splice variants of the single Slo -subunit. Here we describe an accessory subunit (3) with homology to other -subunits of BK channels that confers inactivation when it is coexpressed with Slo. Message encoding the 3 subunit is found in rat insulinoma tumor (RINm5f) cells and adrenal chromaffin cells, both of which express inactivating BK channels. Channels resulting from coexpression of Slo  and 3 subunits exhibit properties characteristic of native inactivating BK channels. Inactivation involves multiple cytosolic, trypsin-sensitive domains. The time constant of inactivation reaches a limiting value ~25-30 msec at Ca²⁺ of 10 µM and positive activation potentials. Unlike Shaker N-terminal inactivation, but like native inactivating BK channels, a cytosolic channel blocker does not compete with the native inactivation process. Finally, the 3 subunit confers a reduced sensitivity to charybdotoxin, as seen with native inactivating BK channels. Inactivation arises from the N terminal of the 3 subunit. Removal of the 3 N terminal (33 amino acids) abolishes inactivation, whereas the addition of the 3 N terminal onto the 1 subunit confers inactivation. The 3 subunit shares with the 1 subunit an ability to shift the range of voltages over which channels are activated at a given Ca²⁺. Thus, the -subunit family of BK channels regulates a number of critical aspects of BK channel phenotype, including inactivation and apparent Ca²⁺ sensitivity.

Key words: accessory subunits; K⁺ channels; BK channels; Ca²⁺- and voltage-gated K⁺ channels; mSlo channels; inactivation

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19135255-10$05.00/0

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