The C Terminus of SUR1 Is Required for Trafficking of KATP Channels

Nidhi Sharma,Ana Crane,John P Clement,Gabriela Gonzalez,Andrey P Babenko,Joseph Bryan,Lydia Aguilar-Bryan

doi:10.1074/jbc.274.29.20628

Nidhi Sharma, Ana Crane + Show 5 more

Open Access

https://doi.org/10.1074/jbc.274.29.20628

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Abstract

In beta cells from the pancreas, ATP-sensitive potassium channels, or KATP channels, are composed of two subunits, SUR1 and KIR6.2, assembled in a (SUR1/KIR6.2)4 stoichiometry. The correct stoichiometry of channels at the cell surface is tightly regulated by the presence of novel endoplasmic reticulum (ER) retention signals in SUR1 and KIR6.2; incompletely assembled KATP channels fail to exit the ER/cis-Golgi compartments. In addition to these retrograde signals, we show that the C terminus of SUR1 has an anterograde signal, composed in part of a dileucine motif and downstream phenylalanine, which is required for KATP channels to exit the ER/cis-Golgi compartments and transit to the cell surface. Deletion of as few as seven amino acids, including the phenylalanine, from SUR1 markedly reduces surface expression of KATP channels. Mutations leading to truncation of the C terminus of SUR1 are one cause of a severe, recessive form of persistent hyperinsulinemic hypoglycemia of infancy. We propose that the complete loss of beta cell KATP channel activity seen in this form of hyperinsulinism is a failure of KATP channels to traffic to the plasma membrane.

Highlights

In pancreatic beta cells, the high affinity sulfonylurea receptor, SUR11, and the potassium inward rectifier, KIR6.2, combine to form octameric ATP-sensitive potassium channels, KATP channels, that link glucose metabolism to membrane potential (1–5)
The SUR1⌬C2 and ⌬C4/KIR6.2 channels show glibenclamide-inhibited 86Rbϩ efflux attributable to KATP channels which is comparable with wild-type channels (Fig. 1A); the SUR1⌬C7/KIR6.2 channels show approximately a 50% decrease in activity, while a complete loss of activity is observed for the SUR1⌬C13, ⌬C22, and ⌬C49/KIR6.2 channels
There were no significant differences in the rates of 86Rbϩ efflux between the SUR1⌬C/ KIR6.2 versus SUR1⌬C/KIR6.2⌬C35 channels (Fig. 1A), indicating that the loss of channel activity resulting from deletion of the C terminus of SUR1 does not depend on the presence of the endoplasmic reticulum retention (ER) retention signal on KIR6.2

Summary

Introduction

The high affinity sulfonylurea receptor, SUR11, and the potassium inward rectifier, KIR6.2, combine to form octameric ATP-sensitive potassium channels, KATP channels, that link glucose metabolism to membrane potential (1–5). We show here that there is an additional level of regulation of trafficking; the C terminus of SUR1 has an anterograde signal that is required for surface expression of KATP channels. Mature SUR1 is present only when the receptor is co-expressed with KIR6.1 or KIR6.2 and has been shown to assemble with KIR6.2 to form active KATP channels in the plasma membrane (3).

Results

Conclusion