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J. Biol. Chem., Vol. 278, Issue 44, 43533-43540, October 31, 2003

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Identification of a Heteromeric Interaction That Influences the Rectification, Gating, and pH Sensitivity of Kir4.1/Kir5.1 Potassium Channels^*

Maria Casamassima, M. Cristina D'Adamo, Mauro Pessia, and Stephen J. Tucker¶||

From the Istituto di Ricerche Farmacologiche "Mario Negri," Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro (Chieti), Italy, the Section of Human Physiology, University of Perugia School of Medicine, 06126 Perugia, Italy, and the ^¶University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, United Kingdom

Heteromultimerization between different potassium channel subunits can generate channels with novel functional properties and thus contributes to the rich functional diversity of this gene family. The inwardly rectifying potassium channel subunit Kir5.1 exhibits highly selective heteromultimerization with Kir4.1 to generate heteromeric Kir4.1/Kir5.1 channels with unique rectification and kinetic properties. These novel channels are also inhibited by intracellular pH within the physiological range and are thought to play a key role in linking K⁺ and H⁺ homeostasis by the kidney. However, the mechanisms that control heteromeric K⁺ channel assembly and the structural elements that generate their unique functional properties are poorly understood. In this study we identify residues at an intersubunit interface between the cytoplasmic domains of Kir5.1 and Kir4.1 that influence the novel rectification and gating properties of heteromeric Kir4.1/Kir5.1 channels and that also contribute to their pH sensitivity. Furthermore, this interaction presents a structural mechanism for the functional coupling of these properties and explains how specific heteromeric interactions can contribute to the novel functional properties observed in heteromeric Kir channels. The highly conserved nature of this structural association between Kir subunits also has implications for understanding the general mechanisms of Kir channel gating and their regulation by intracellular pH.

Received for publication, June 20, 2003 , and in revised form, August 4, 2003.

^* This work was supported in part by the Royal Society and the National Kidney Research Fund (United Kingdom), Ministero dell'Istruzione dell'Università e della Ricerca (MIUR) Grants FIRB (RBAU01TJ93) and L. 488/92 Project number S209-P/F (Italy). 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.

^|| Royal Society University Research Fellow. To whom correspondence should be addressed. E-mail: stephen.tucker{at}physiol.ox.ac.uk.

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