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J. Biol. Chem., Vol. 282, Issue 5, 3231-3240, February 2, 2007

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Activation of NFATc3 Down-regulates the 1 Subunit of Large Conductance, Calcium-activated K⁺ Channels in Arterial Smooth Muscle and Contributes to Hypertension^*

Madeline Nieves-Cintrón, Gregory C. Amberg, C. Blake Nichols, Jeffery D. Molkentin, and Luis F. Santana¹

From the Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195 and Children's Hospital Medical Center for Molecular Cardiovascular Biology, Cincinnati, Ohio 45229-3039

Large conductance, Ca²⁺-activated K⁺ (BK) channels modulate the excitability and contractile state of arterial smooth muscle. Recently, we demonstrated that during hypertension, expression of the accessory 1 subunit was decreased relative to the pore-forming subunit of the BK channel. Reduced 1 subunit expression resulted in BK channels with impaired function due to lowered sensitivity to Ca²⁺. Here, we tested the hypothesis that activation of the calcineurin/NFATc3 signaling pathway down-regulates 1 expression during angiotensin II-induced hypertension. Consistent with this hypothesis, we found that in vivo administration of angiotensin II-activated calcineurin/NFATc3 signaling in arterial smooth muscle. During angiotensin II infusion, arterial smooth muscle BK channel function was decreased in wild type (WT) but not in NFATc3 null (NFATc3^-/-) mice. Accordingly, 1 expression was decreased in WT but not in NFATc3^-/- arteries. Angiotensin II-induced down-regulation of the 1 subunit required Ca²⁺ influx via L-type Ca²⁺ channels. However, in the absence of angiotensin II, moderate elevation of [Ca²⁺]_i alone was not sufficient to activate NFAT transcriptional activity and, thus, decrease 1 subunit expression. Importantly, angiotensin II infusion increased systemic blood pressure to a lower extent in NFATc3^-/- than in WT mice, indicating that this transcription factor is required for the development of severe hypertension during chronic angiotensin II signaling activation. We conclude that activation of calcineurin and NFATc3 during sustained angiotensin II signaling down-regulates the expression of the 1 subunit of the BK channel, which in turn contributes to arterial dysfunction and the development of hypertension.

Received for publication, September 12, 2006 , and in revised form, November 27, 2006.

^* This work was supported by National Institutes of Health Grants HL077115 and HL085870. 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.

¹ To whom correspondence should be addressed: Dept. of Physiology and Biophysics, University of Washington, Box 357290, Seattle, WA 98195. Tel.: 206-543-0986; Fax: 206-685-0619; E-mail: santana{at}u.washington.edu.

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