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J. Biol. Chem., Vol. 282, Issue 34, 24563-24573, August 24, 2007

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Female Gender-specific Inhibition of KCNQ1 Channels and Chloride Secretion by 17-Estradiol in Rat Distal Colonic Crypts^*

From the Department of Molecular Medicine, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin 9, Ireland

The estrogen sex steroid 17-estradiol rapidly inhibits secretagogue-stimulated cAMP-dependent Cl^– secretion in the female rat distal colonic crypt by the inhibition of basolateral K⁺ channels. In Ussing chamber studies, both the anti-secretory response and inhibition of basolateral K⁺ current was shown to be attenuated by pretreatment with rottlerin, a PKC-specific inhibitor. In whole cell patch-clamp analysis, 17-estradiol inhibited a chromanol 293B-sensitive KCNQ1 channel current in isolated female rat distal colonic crypts. Estrogen had no effect on KCNQ1 channel currents in colonic crypts isolated from male rats. Female distal colonic crypts expressed a significantly higher amount of PKC in comparison to male tissue. PKC and PKA were activated at 5 min in response to 17-estradiol in female distal colonic crypts only. Both PKC- and PKA-associated with the KCNQ1 channel in response to 17-estradiol in female distal colonic crypts, and no associations were observed in crypts from males. PKA activation, association with KCNQ1, and phosphorylation of the channel were regulated by PKC as the responses were blocked by pretreatment with rottlerin. Taken together, our experiments have identified the molecular targets underlying the anti-secretory response to estrogen involving the inhibition of KCNQ1 channel activity via PKC- and PKA-dependent signaling pathways. This is a novel gender-specific mechanism of regulation of an ion channel by estrogen. The anti-secretory response described in this study provides molecular insights whereby estrogen causes fluid retention effects in the female during periods of high circulating plasma estrogen levels.

Received for publication, December 21, 2006 , and in revised form, May 29, 2007.

^* This work was supported in part by The Wellcome Trust Programme Grant 06089/Z/00/Z and Higher Education Authority of Ireland (HEA) PRTLI Grants Cycle 1 and 3. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

² Recipient of a Wellcome Trust Studentship Prize 06379/Z/01/Z.

¹ To whom correspondence should be addressed: Dept. of Molecular Medicine, Royal College of Surgeons in Ireland, Smurfit Bldg., Beaumont Hospital, PO Box 9063, Dublin 9, Ireland. Tel.: 00-353-1-8093824; Fax: 00-353-1-8093778; E-mail: fomahony{at}rcsi.ie.

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