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J Neurophysiol (January 25, 2006). doi:10.1152/jn.01352.2005
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Submitted on December 22, 2005
Accepted on January 24, 2006

{beta}2 and {beta}4 Subunits of BK Channels Confer Differential Sensitivity to Acute Modulation by Steroid Hormones

Jonathan T. King1, Peter V. Lovell1, Mark Rishniw2, Michael I. Kotlikoff2, Mary Lou Zeeman3, and David P. McCobb1*

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 {beta}1 subunits. We demonstrate here that 1) multiple members of the {beta} family confer sensitivity to multiple steroids on BK channels, 2) that {beta} subunits differentiate between steroids, and 3) that different {beta}s have distinct relative preferences for particular steroids. Expressed in HEK 293 cells, inside-out patches with channels composed of Slo-{alpha} alone showed no steroid sensitivity. Cells expressing {alpha}{beta}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, {alpha}{beta}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 {beta}2 or {beta}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-{beta} 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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