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Sequence analysis of large-conductance Ca<jats:sup>2+<\/jats:sup>-activated K<jats:sup>+<\/jats:sup> (BK) channels revealed a putative 14-3-3 binding site in the COOH-terminal region. Our previous data showed that 14-3-3\u03b3 is widely expressed in the mouse kidney. Therefore, we hypothesized that 14-3-3\u03b3 has a novel role in the regulation of BK channel activity and protein expression. We used electrophysiology, Western blot analysis, and coimmunoprecipitation to examine the effects of 14-3-3\u03b3 on BK channels both in vitro and in vivo. We demonstrated the interaction of 14-3-3\u03b3 with BK \u03b1-subunits (BK\u03b1) by coimmunoprecipitation. In human embryonic kidney-293 cells stably expressing BK\u03b1, overexpression of 14-3-3\u03b3 significantly decreased BK channel activity and channel open probability. 14-3-3\u03b3 inhibited both total and cell surface BK\u03b1 protein expression while enhancing ERK1\/2 phosphorylation in Cos-7 cells cotransfected with flag-14-3-3\u03b3 and myc-BK. Knockdown of 14-3-3\u03b3 by siRNA transfection markedly increased BK\u03b1 expression. Blockade of the ERK1\/2 pathway by incubation with the MEK-specific inhibitor U0126 partially abolished 14-3-3\u03b3-mediated inhibition of BK protein expression. Similarly, pretreatment of the lysosomal inhibitor bafilomycin A1 reversed the inhibitory effects of 14-3-3\u03b3 on BK protein expression. Furthermore, overexpression of 14-3-3\u03b3 significantly increased BK protein ubiquitination in embryonic kidney-293 cells stably expressing BK\u03b1. Additionally, 3 days of dietary K<jats:sup>+<\/jats:sup> challenge reduced 14-3-3\u03b3 expression and ERK1\/2 phosphorylation while enhancing renal BK protein expression and K<jats:sup>+<\/jats:sup> excretion. These data suggest that 14-3-3\u03b3 modulates BK channel activity and protein expression through an ERK1\/2-mediated ubiquitin-lysosomal pathway. <\/jats:p>","DOI":"10.1152\/ajprenal.00584.2019","type":"journal-article","created":{"date-parts":[[2020,5,28]],"date-time":"2020-05-28T16:02:26Z","timestamp":1590681746000},"page":"F52-F62","source":"Crossref","is-referenced-by-count":4,"title":["14-3-3\u03b3, a novel regulator of the large-conductance Ca<sup>2+<\/sup>-activated K<sup>+<\/sup> channel"],"prefix":"10.1152","volume":"319","author":[{"given":"Shan","family":"Chen","sequence":"first","affiliation":[{"name":"Renal Divison, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia"},{"name":"Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiuyan","family":"Feng","sequence":"additional","affiliation":[{"name":"Renal 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