Shear stress triggers insertion of voltage-gated potassium channels from intracellular compartments in atrial myocytes

Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):E3955-64. doi: 10.1073/pnas.1309896110. Epub 2013 Sep 24.

Abstract

Atrial myocytes are continuously exposed to mechanical forces including shear stress. However, in atrial myocytes, the effects of shear stress are poorly understood, particularly with respect to its effect on ion channel function. Here, we report that shear stress activated a large outward current from rat atrial myocytes, with a parallel decrease in action potential duration. The main ion channel underlying the increase in current was found to be Kv1.5, the recruitment of which could be directly observed by total internal reflection fluorescence microscopy, in response to shear stress. The effect was primarily attributable to recruitment of intracellular pools of Kv1.5 to the sarcolemma, as the response was prevented by the SNARE protein inhibitor N-ethylmaleimide and the calcium chelator BAPTA. The process required integrin signaling through focal adhesion kinase and relied on an intact microtubule system. Furthermore, in a rat model of chronic hemodynamic overload, myocytes showed an increase in basal current despite a decrease in Kv1.5 protein expression, with a reduced response to shear stress. Additionally, integrin beta1d expression and focal adhesion kinase activation were increased in this model. This data suggests that, under conditions of chronically increased mechanical stress, the integrin signaling pathway is overactivated, leading to increased functional Kv1.5 at the membrane and reducing the capacity of cells to further respond to mechanical challenge. Thus, pools of Kv1.5 may comprise an inducible reservoir that can facilitate the repolarization of the atrium under conditions of excessive mechanical stress.

Keywords: cardiomyocytes; potassium current; trafficking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Biomechanical Phenomena
  • Blotting, Western
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Ethylmaleimide / pharmacology
  • Fluorescent Antibody Technique
  • Heart Atria / cytology*
  • Integrin beta1 / metabolism
  • Kv1.5 Potassium Channel / metabolism*
  • Male
  • Microscopy, Fluorescence
  • Models, Biological
  • Myocytes, Cardiac / metabolism*
  • Patch-Clamp Techniques
  • Rats
  • Rats, Wistar
  • SNARE Proteins / antagonists & inhibitors
  • Sarcolemma / metabolism
  • Shear Strength
  • Signal Transduction / physiology*
  • Stress, Physiological / physiology*

Substances

  • Integrin beta1
  • Kv1.5 Potassium Channel
  • SNARE Proteins
  • Egtazic Acid
  • 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
  • Ethylmaleimide