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J. Biol. Chem., Vol. 283, Issue 14, 8778-8782, April 4, 2008

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A Novel ABCC8 (SUR1)-dependent Mechanism of Metabolism-Excitation Uncoupling^*

From the Pacific Northwest Research Institute, Seattle, Washington 98122

ATP/ADP-sensing (sulfonylurea receptor (SUR)/K_IR6)₄ K_ATP channels regulate the excitability of our insulin secreting and other vital cells via the differential MgATP/ADP-dependent stimulatory actions of their tissue-specific ATP-binding cassette regulatory subunits (sulfonylurea receptors), which counterbalance the nearly constant inhibitory action of ATP on the K⁺ inwardly rectifying pore. Mutations in SUR1 that abolish its stimulation have been found in infants persistently releasing insulin. Activating mutations in SUR1 have been shown to cause neonatal diabetes. Here, analyses of K_IR6.2-based channels with diabetogenic receptors reveal that MgATP-dependent hyper-stimulation of mutant SUR can compromise the ability of K_ATP channels to function as metabolic sensors. I demonstrate that the channel hyperactivity rises exponentially with the number of hyperstimulating subunits, so small subpopulations of channels with more than two mutant SUR can dominate hyperpolarizing currents in heterozygous patients. I uncovered an attenuated tolbutamide inhibition of the hyperstimulated mutant, which is normally sensitive to the drug under non-stimulatory conditions. These findings show the key role of SUR in sensing the metabolic index in humans and urge others to (re)test mutant SUR/K_IR6 channels from probands in physiologic MgATP.

Received for publication, December 31, 2007 , and in revised form, February 13, 2008.

^* This work was supported by grants from American Heart Association and NIDDK, National Institutes of Health. 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 three supplemental figures and a supplemental table, as well as supplemental references.

¹ To whom correspondence should be addressed: 720 Broadway, Seattle, WA 98122; Tel.: 206-568-1473; Fax: 206-726-1217; E-mail: ababenko{at}pnri.org.

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