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J. Biol. Chem., Vol. 280, Issue 19, 19097-19104, May 13, 2005

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Molecular Determinants of Cardiac K_ATP Channel Activation by Epoxyeicosatrienoic Acids^*

Tong Lu, Min-Pyo Hong, and Hon-Chi Lee

From the Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905

We have previously reported that epoxyeicosatrienoic acids (EETs), the cytochrome P450 epoxygenase metabolites of arachidonic acid, are potent stereospecific activators of the cardiac K_ATP channel. The epoxide group in EET is critical for reducing channel sensitivity to ATP, thereby activating the channel. This study is to identify the molecular sites on the K_ATP channels for EET-mediated activation. We investigated the effects of EETs on Kir6.2C26 with or without the coexpression of SUR2A and on Kir6.2 mutants of positively charged residues known to affect channel activity coexpressed with SUR2A in HEK293 cells. The ATP IC₅₀ values were significantly increased in Kir6.2 R27A, R50A, K185A, and R201A but not in R16A, K47A, R54A, K67A, R192A, R195A, K207A, K222A, and R314A mutants. Similar to native cardiac K_ATP channel, 5 µM 11,12-EET increased the ATP IC₅₀ by 9.6-fold in Kir6.2/SUR2A wild type and 8.4-fold in Kir6.2C26. 8,9- and 14,15-EET regioisomers activated the Kir6.2 channel as potently as 11,12-EET. 8,9- and 11,12-EET failed to change the ATP sensitivity of Kir6.2 K185A, R195A, and R201A, whereas their effects were intact in the other mutants. 14,15-EET had a similar effect with K185A and R201A mutants, but instead of R195A, it failed to activate Kir6.2R192A. These results indicate that activation of Kir6.2 by EETs does not require the SUR2A subunit, and the region in the Kir6.2 C terminus from Lys-185 to Arg-201 plays a critical role in EET-mediated Kir6.2 channel activation. Based on computer modeling of the Kir6.2 structure, we infer that the EET-Kir6.2 interaction may allosterically change the ATP binding site on Kir6.2, reducing the channel sensitivity to ATP.

Received for publication, December 14, 2004 , and in revised form, February 15, 2005.

^* This work was supported by American Heart Association Grant-in-aid 0265472Z (to T. L.) and National Institutes of Health Grants HL-63754 and HL-74180 (to H.-C. L). 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.

To whom correspondence should be addressed: Division of Cardiovascular Diseases, Dept. of Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Tel.: 507-255-9903; Fax: 507-255-7070; E-mail: Lu.tong{at}mayo.edu.

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