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2 and 4 Subunits of BK Channels Confer Differential Sensitivity to Acute Modulation by Steroid Hormones
1 Neurobiology and Behavior, Cornell University, Ithaca, NY, USA
2 Biomedical Sciences, Cornell University, Ithaca, NY, USA
3 Applied Mathematics, University of Texas at San Antonio, San Antonio, TX, USA
* To whom correspondence should be addressed. E-mail: dpm9{at}cornell.edu.
Membrane-associated receptors for rapid, steroidal neuromodulation remain elusive. Estradiol has been reported to facilitate activation of voltage- and calcium-dependent "BK" potassium channels encoded by Slo, if associated with 
1 subunits. We demonstrate 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 a 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.
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