The C terminus of SUR1 is required for trafficking of K(ATP) channels

Abstract

In beta cells from the pancreas, ATP-sensitive potassium channels, or K(ATP) channels, are composed of two subunits, SUR1 and K(IR)6.2, assembled in a (SUR1/K(IR)6.2)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 K(IR)6.2; incompletely assembled K(ATP) 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 K(ATP) 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 K(ATP) 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 K(ATP) channel activity seen in this form of hyperinsulinism is a failure of K(ATP) channels to traffic to the plasma membrane.