Adult Ventricular Myocytes Segregate KCNQ1 and KCNE1 to Keep the IKs Amplitude in Check Until When Larger IKs Is Needed

Circ Arrhythm Electrophysiol. 2017 Jun;10(6):e005084. doi: 10.1161/CIRCEP.117.005084.

Abstract

Background: KCNQ1 and KCNE1 assemble to form the slow delayed rectifier (IKs) channel critical for shortening ventricular action potentials during high β-adrenergic tone. However, too much IKs under basal conditions poses an arrhythmogenic risk. Our objective is to understand how adult ventricular myocytes regulate the IKs amplitudes under basal conditions and in response to stress.

Methods and results: We express fluorescently tagged KCNQ1 and KCNE1 in adult ventricular myocytes and follow their biogenesis and trafficking paths. We also study the distribution patterns of native KCNQ1 and KCNE1, and their relationship to IKs amplitudes, in chronically stressed ventricular myocytes, and use COS-7 cell expression to probe the underlying mechanism. We show that KCNQ1 and KCNE1 are both translated in the perinuclear region but traffic by different routes, independent of each other, to their separate subcellular locations. KCNQ1 mainly resides in the jSR (junctional sarcoplasmic reticulum), whereas KCNE1 resides on the cell surface. Under basal conditions, only a small portion of KCNQ1 reaches the cell surface to support the IKs function. However, in response to chronic stress, KCNQ1 traffics from jSR to the cell surface to boost the IKs amplitude in a process depending on Ca binding to CaM (calmodulin).

Conclusions: In adult ventricular myocytes, KCNE1 maintains a stable presence on the cell surface, whereas KCNQ1 is dynamic in its localization. KCNQ1 is largely in an intracellular reservoir under basal conditions but can traffic to the cell surface and boost the IKs amplitude in response to stress.

Keywords: action potentials; calcium; calmodulin; potassium channels; sarcoplasmic reticulum.

MeSH terms

  • Action Potentials
  • Animals
  • COS Cells
  • Calmodulin / metabolism
  • Cell Membrane / metabolism
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Dogs
  • Guinea Pigs
  • Heart Ventricles / metabolism*
  • Heart Ventricles / physiopathology
  • Hypertension / metabolism*
  • Hypertension / physiopathology
  • Intermediate-Conductance Calcium-Activated Potassium Channels / metabolism*
  • KCNQ1 Potassium Channel / biosynthesis
  • KCNQ1 Potassium Channel / genetics
  • KCNQ1 Potassium Channel / metabolism*
  • Myocytes, Cardiac / metabolism*
  • Potassium / metabolism*
  • Potassium Channels, Voltage-Gated / biosynthesis
  • Potassium Channels, Voltage-Gated / genetics
  • Potassium Channels, Voltage-Gated / metabolism*
  • Protein Transport
  • Rats, Inbred SHR
  • Sarcoplasmic Reticulum / metabolism
  • Time Factors
  • Transfection

Substances

  • Calmodulin
  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • KCNQ1 Potassium Channel
  • Kcne1 protein, rat
  • Kcnq1 protein, rat
  • Potassium Channels, Voltage-Gated
  • Potassium