the brain-specific beta4 subunit downregulates bk channel cell surface expression的brain-specific beta4 bk通道亚基会使细胞表面表达.pdfVIP

The Brain-Specific Beta4 Subunit Downregulates BK Channel Cell Surface Expression 1¤a 1 2¤b 3 2 Sonal Shruti , Joanna Urban-Ciecko , James A. Fitzpatrick , Robert Brenner , Marcel P. Bruchez *, Alison L. Barth1* 1 Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America, 2 Molecular and Biosensor Imaging Center, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America, 3 Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America Abstract The large-conductance K+ channel (BK channel) can control neural excitability, and enhanced channel currents facilitate high firing rates in cortical neurons. The brain-specific auxiliary subunit b4 alters channel Ca++- and voltage-sensitivity, and b4 knock-out animals exhibit spontaneous seizures. Here we investigate b4’s effect on BK channel trafficking to the plasma membrane. Using a novel genetic tag to track the cellular location of the pore-forming BKa subunit in living cells, we find that b4 expression profoundly reduces surface localization of BK channels via a C-terminal ER retention sequence. In hippocampal CA3 neurons from C57BL/6 mice with endogenously high b4 expression, whole-cell BK channel currents display none of the characteristic properties of BKa+ b4 channels observed in heterologous cells. Finally, b4 knock-out animals exhibit a 2.5-fold increase in whole-cell BK channel current, indicating that b4 also regulates current magnitude in vivo. Thus, we propose that a major function of the brain-specific b4 subunit in CA3 neurons