title: The brain-specific Beta4 subunit downregulates BK channel cell surface expression.
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 β4 alters channel Ca(++)- and voltage-sensitivity, and β4 knock-out animals exhibit spontaneous seizures. Here we investigate β4's effect on BK channel trafficking to the plasma membrane. Using a novel genetic tag to track the cellular location of the pore-forming BKα subunit in living cells, we find that β4 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 β4 expression, whole-cell BK channel currents display none of the characteristic properties of BKα+β4 channels observed in heterologous cells. Finally, β4 knock-out animals exhibit a 2.5-fold increase in whole-cell BK channel current, indicating that β4 also regulates current magnitude in vivo. Thus, we propose that a major function of the brain-specific β4 subunit in CA3 neurons is control of surface trafficking.
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Sonal
authors.initials: S
authors.lastname: Shruti
authors.forename: Joanna
authors.initials: J
authors.lastname: Urban-Ciecko
authors.forename: James A
authors.initials: JA
authors.lastname: Fitzpatrick
authors.forename: Robert
authors.initials: R
authors.lastname: Brenner
authors.forename: Marcel P
authors.initials: MP
authors.lastname: Bruchez
authors.forename: Alison L
authors.initials: AL
authors.lastname: Barth
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D056654:CA3 Region, Hippocampal / Q000378:metabolism; D020013:Calcium Signaling; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation; D055724:Electrophysiological Phenomena; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008959:Models, Neurological; D021122:Protein Subunits; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D021122:Protein Subunits; D011994:Recombinant Proteins