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

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.