The c terminus of SUR1 is required for trafficking of KKATP 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 assemb led 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 ant erograde signal, composed in part of a dileucine motif and downstream pheny lalanine, which is required for K-ATP channels to exit the ER/cis-Golgi com partments and transit to the cell surface. Deletion of as few as seven amin o acids, including the phenylalanine, from SUR1 markedly reduces surface ex pression of K-ATP channels. Mutations leading to truncation of the C termin us of SUR1 are one cause of a severe, recessive form of persistent hyperins ulinemic hypoglycemia of infancy. We propose that the complete loss of beta cell K-ATP channel activity seen in this form of hyperinsulinism is a fail ure of K-ATP channels to traffic to the plasma membrane.