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J. Biol. Chem., Vol. 282, Issue 8, 5781-5789, February 23, 2007

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An Andersen-Tawil Syndrome Mutation in Kir2.1 (V302M) Alters the G-loop Cytoplasmic K⁺ Conduction Pathway^*

From the Departments of Physiology and Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201

Loss-of-function mutations in the inward rectifier potassium channel, Kir2.1, cause Andersen-Tawil syndrome (ATS-1), an inherited disorder of periodic paralysis and ventricular arrhythmias. Here, we explore the mechanism by which a specific ATS-1 mutation (V302M) alters channel function. Val-302 is located in the G-loop, a structure that is believed to form a flexible barrier for potassium permeation at the apex of the cytoplasmic pore. Consistent with a role in stabilizing the G-loop in an open conformation, we found the V302M mutation specifically renders the channel unable to conduct potassium without altering subunit assembly or attenuating cell surface expression. As predicted by the position of the Val-302 side chain in the crystal structure, amino acid substitution analysis revealed that channel activity and phosphatidylinositol 4,5-bisphosphate (PIP2) sensitivity are profoundly sensitive to alterations in the size, shape, and hydrophobicity of side chains at the Val-302 position. The observations establish that the Val-302 side chain is a critical determinant of potassium conduction through the G-loop. Based on our functional studies and the cytoplasmic domain crystal structure, we suggest that Val-302 may influence PIP2 gating indirectly by translating PIP2 binding to conformational changes in the G-loop pore.

Received for publication, September 11, 2006 , and in revised form, December 8, 2006.

^* This project was supported by National Institutes of Health Grants P01 HL70709 and R01 DK54231. 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. Tel.: 410-706-3851; Fax: 410-706-8341; E-mail: pwelling{at}umaryland.edu.

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