Selective Golgi export of Kir2.1 controls the stoichiometry of functional Kir2.x channel heteromers

Alexis Hofherr,Nikolaj KlöCker,Bernd Fakler

doi:10.1242/jcs.02322

Abstract

Surface expression of ion channels and receptors often depends on intrinsic sequence motifs that control their intracellular transport along the secretory pathway. Although members of the Kir2.x subfamily share two such motifs - a diacidic ER export motif and a positively charged Golgi export motif - they strongly differ in their surface expression. Whereas Kir2.1 shows prominent plasma membrane localization, Kir2.4 channels accumulate within the Golgi complex. By constructing chimeras between Kir2.1 and Kir2.4 subunits, a stretch of 20 amino acids was identified in the Kir2.1 C-terminus that is both necessary and sufficient to promote anterograde transport of Kir channel subunits at the level of trafficking from the Golgi to the plasma membrane. The core element of the identified sequence bears a tyrosine-dependent YXXPhi consensus motif for adaptin binding, with the flanking residues determining its functional efficiency. As the signal is dominant in promoting surface transport of Kir2.1/Kir2.4 channel heteromers and is recognized by both the epithelial and neuronal intracellular sorting machinery, the preferential Golgi export of Kir2.1 will control the stoichiometry of Kir2.x heteromers expressed on the cell surface.

Highlights

Rectifying potassium (Kir) channels exert diverse cellular functions, such as controlling membrane excitability, heart rate, hormone release and neuronal signal transduction (Hille, 1992)
Members of the Kir2.x subfamily share two such motifs – a diacidic endoplasmic reticulum (ER) export motif and a positively charged Golgi export motif – they strongly differ in their surface expression
By constructing chimeras between Kir2.1 and Kir2.4 subunits, a stretch of 20 amino acids was identified in the Kir2.1 C-terminus that is both necessary and sufficient to promote anterograde transport of Kir channel subunits at the level of trafficking from the Golgi to the plasma membrane

Summary

Introduction

Rectifying potassium (Kir) channels exert diverse cellular functions, such as controlling membrane excitability, heart rate, hormone release and neuronal signal transduction (Hille, 1992). Seven subfamilies of Kir channels have been identified based on sequence similarity and functional properties (Doupnik et al, 1995; Fakler and Ruppersberg, 1996; Nichols and Lopatin, 1997; Krapivinsky et al, 1998; Döring et al, 1998). Members of the Kir2.x subfamily share the biophysical characteristic of strong inward rectification that is due to a highly voltage-dependent block of the channel pore by intracellular polyamines and Mg2+ (Lopatin et al, 1994; Fakler et al, 1995). Voltage-dependent inward rectification enables Kir2.x channels to stabilize the resting membrane potential near the K+ equilibrium potential and prevents them from shunting action potentials. The expression patterns and the functional diversity of native inward-rectifier K+ currents suggest that channels may form heteromers. Heteromultimerization may contribute to the heterogeneous phenotype of Andersen’s syndrome, a

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