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,Stephen J Tucker

doi:10.1074/jbc.m306596200

Abstract

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.

Highlights

Heteromultimerization between different potassium channel subunits can generate channels with novel functional properties and contributes to the rich functional diversity of this gene family
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 contribute to their pH sensitivity
The ability of Kir subunits to heteromultimerize with Kir5.1 is highly restricted, only Kir4.1 and Kir4.2 physically associate with Kir5.1 and we have recently shown that a small domain within the C terminus of Kir4.1 contributes to the specificity of this interaction [13]

Summary

Introduction

Heteromultimerization between different potassium channel subunits can generate channels with novel functional properties and 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 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. A key property of these Kir1.1, Kir4.0, and heteromeric Kir4.0/Kir5.1 channels is their inhibition by Hϩ within the physiological range, making them highly sensitive linkers between Kϩ and Hϩ homeostasis [5,6,7,8,9,10] This functional linkage allows coordinate regulation of both apical and basolateral Kϩ channels, as well as providing a mechanism to prevent excessive loss of Kϩ during metabolic acidosis [3]. For these cells to maintain distinct subpopulations of both homo- and heteromeric Kir channels it is essential that mechanisms exist to prevent random or promiscuous interactions

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Results

Conclusion