beta2 and beta4 Subunits of BK Channels Confer Differential Sensitivity to Acute Modulation by Steroid Hormones

1 Department of Neurobiology and Behavior and 2 Department of Biomedical Sciences, Cornell University, Ithaca, New York: and 3 Department of Applied Mathematics, University of Texas, San Antonio, Texas Submitted 22 December 2005; accepted in final form 24 January 2006 Membrane-associated receptors for rapid, steroidal neuromodulation remain elusive. Estradiol has been reported to facilitate activation of voltage- and Ca 2+ -dependent BK potassium channels encoded by Slo , if associated with 1 subunits. We show here that 1 ) multiple members of the family confer sensitivity to multiple steroids on BK channels, 2 ) that subunits differentiate between steroids, and 3 ) that different s have distinct relative preferences for particular steroids. Expressed in HEK 293 cells, inside-out patches with channels composed of Slo - alone showed no steroid sensitivity. Cells expressing 4 exhibited potent, rapid, reversible, and dose-dependent potentiation by corticosterone (CORT; a glucocorticoid), and were potentiated to a lesser degree by other sex and stress steroids. In contrast, 2 channels were potentiated more strongly by dehydroepiandrosterone (DHEA; an enigmatic, stress-related adrenal androgen), and to a lesser extent by CORT, estradiol, testosterone, and DHEA-S. Cholesterol had no effect on any BK channel compositions tested. Conductance–voltage plots of channels composed of plus 2 or 4 subunits were shifted in the negative direction by steroids, indicating greater activation at negative voltages. Thus our results argue that the variety of Slo - subunit coexpression patterns occurring in vivo expands the repertoire of Slo channel gating in yet another dimension not fully appreciated, rendering BK gating responsive to dynamic fluctuations in a multiple of steroid hormones. Address for reprint requests and other correspondence: D. P. McCobb, Dept. of Neurobiology and Behavior, W153 Mudd Hall, Cornell Univ., Ithaca, NY 14853 (E-mail: dpm9{at}cornell.edu )