Sulfonylureas Correct Trafficking Defects of Disease-causing ATP-sensitive Potassium Channels by Binding to the Channel Complex

Fei-Fei Yan,Jillene Casey,Show-Ling Shyng

doi:10.1074/jbc.m605195200

Fei-Fei Yan, Jillene Casey + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m605195200

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Abstract

ATP-sensitive potassium (K(ATP)) channels mediate glucose-induced insulin secretion by coupling metabolic signals to beta-cell membrane potential and the secretory machinery. Reduced K(ATP) channel expression caused by mutations in the channel proteins: sulfonylurea receptor 1 (SUR1) and Kir6.2, results in loss of channel function as seen in congenital hyperinsulinism. Previously, we reported that sulfonylureas, oral hypoglycemic drugs widely used to treat type II diabetes, correct the endoplasmic reticulum to the plasma membrane trafficking defect caused by two SUR1 mutations, A116P and V187D. In this study, we investigated the mechanism by which sulfonylureas rescue these mutants. We found that glinides, another class of SUR-binding hypoglycemic drugs, also markedly increased surface expression of the trafficking mutants. Attenuating or abolishing the ability of mutant SUR1 to bind sulfonylureas or glinides by the following mutations: Y230A, S1238Y, or both, accordingly diminished the rescuing effects of the drugs. Interestingly, rescue of the trafficking defects requires mutant SUR1 to be co-expressed with Kir6.2, suggesting that the channel complex, rather than SUR1 alone, is the drug target. Observations that sulfonylureas also reverse trafficking defects caused by neonatal diabetes-associated Kir6.2 mutations in a way that is dependent on intact sulfonylurea binding sites in SUR1 further support this notion. Our results provide insight into the mechanistic and structural basis on which sulfonylureas rescue K(ATP) channel surface expression defects caused by channel mutations.

Highlights

In congenital hyperinsulinism, two prominent mechanisms accounting for loss of channel function are loss of channel expression at the cell surface and loss of channel sensitivity to stimulation by MgADP [7]
We recently showed that some permanent neonatal diabetes mellitus (PNDM)-causing Kir6.2 mutations reduce the efficiency of channel expression at the cell surface, the loss of expression effect is masked by the ATP gating defect, resulting in a net gain of channel function, thereby the diabetes phenotype [10]
We have previously reported that sulfonylureas rescue surface expression defects of KATP channels caused by two congenital hyperinsulinism (CHI)-associated sulfonylurea receptor 1 (SUR1) mutations, A116P and V187D [23]

Summary

Introduction

Two prominent mechanisms accounting for loss of channel function are loss of channel expression at the cell surface and loss of channel sensitivity to stimulation by MgADP [7]. We recently showed that some PNDM-causing Kir6.2 mutations reduce the efficiency of channel expression at the cell surface, the loss of expression effect is masked by the ATP gating defect, resulting in a net gain of channel function, thereby the diabetes phenotype [10]. Sulfonylureas such as tolbutamide and glibenclamide are oral hypoglycemic drugs commonly used for treating type II diabetes; they do so by binding to the channel, primarily to the SUR1 subunit, and inhibiting channel activity [4, 11, 12]. Deletion of this cytoplasmic loop leads to loss of [3H]glibenclamide binding in recombinant SUR1 expressed in insect cells [21] and mutation of tyrosine 230 in L0 to alanine

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