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

TY - JOUR

T1 - Tuning the electrical properties of the heart by differential trafficking of KATP ion channel complexes

AU - Arakel, Eric C

AU - Brandenburg, Sören

AU - Uchida, Keita

AU - Zhang, Haixia

AU - Lin, Yu-Wen

AU - Kohl, Tobias

AU - Schrul, Bianca

AU - Sulkin, Matthew S

AU - Efimov, Igor R

AU - Nichols, Colin G

AU - Lehnart, Stephan E

AU - Schwappach, Blanche

PY - 2014/5/1

Y1 - 2014/5/1

N2 - The copy number of membrane proteins at the cell surface is tightly regulated. Many ion channels and receptors present retrieval motifs to COPI vesicle coats and are retained in the early secretory pathway. In some cases, the interaction with COPI is prevented by binding to 14-3-3 proteins. However, the functional significance of this antagonism between COPI and 14-3-3 in terminally differentiated cells is unknown. Here, we show that ATP-sensitive K(+) (KATP) channels, which are 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 to COPI and, thereby, silences the arginine-based retrieval signal. Thus, activation of the sympathetic nervous system releases this population of KATP channels from storage in the Golgi and, hence, might facilitate the adaptive response to metabolic challenges.

AB - The copy number of membrane proteins at the cell surface is tightly regulated. Many ion channels and receptors present retrieval motifs to COPI vesicle coats and are retained in the early secretory pathway. In some cases, the interaction with COPI is prevented by binding to 14-3-3 proteins. However, the functional significance of this antagonism between COPI and 14-3-3 in terminally differentiated cells is unknown. Here, we show that ATP-sensitive K(+) (KATP) channels, which are 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 to COPI and, thereby, silences the arginine-based retrieval signal. Thus, activation of the sympathetic nervous system releases this population of KATP channels from storage in the Golgi and, hence, might facilitate the adaptive response to metabolic challenges.

KW - 14-3-3 Proteins/metabolism

KW - Animals

KW - Blotting, Western

KW - Cells, Cultured

KW - Chromatography, Affinity

KW - Electrophysiology

KW - Fluorescent Antibody Technique, Indirect

KW - Immunoprecipitation

KW - KATP Channels/metabolism

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Potassium Channels, Inwardly Rectifying/metabolism

KW - Protein Transport/physiology

KW - Sulfonylurea Receptors/metabolism

U2 - 10.1242/jcs.141440

DO - 10.1242/jcs.141440

M3 - SCORING: Journal article

C2 - 24569881

VL - 127

SP - 2106

EP - 2119

JO - J CELL SCI

JF - J CELL SCI

SN - 0021-9533

IS - Pt 9

ER -