Tuning the electrical properties of the heart by differential trafficking of KATP ion channel complexes

Abstract

The copy number of membrane proteins at the cell surface is tightly regulated. Many ion channels and receptors present retrieval motifs to COPI and are retained in the early secretory pathway. In some cases the COPI interaction is prevented by binding of 14-3-3 proteins. However, the functional significance of this COPI/14-3-3 antagonism in terminally differentiated cells is unknown. Here we show that ATP-sensitive potassium (KATP) channels composed of Kir6.2 and SUR1 subunits are stalled in the Golgi complex of ventricular, but not atrial cardiomyocytes. Upon sustained β-adrenergic stimulation, which leads to activation of protein-kinase A (PKA), SUR1-containing channels reach the plasma membrane of ventricular cells. We show that PKA-dependent phosphorylation of the C-terminus of Kir6.2 decreases binding of COPI and thereby silences the Arg-based retrieval signal. Thus, activation of the sympathetic nervous system releases this KATP channel population from storage in the Golgi and hence may facilitate the adaptive response to metabolic challenges.