Abstract 16308: Shear Stress triggers an Integrin-Dependent Recruitment of Potassium Channels to the Plasma Membrane of Atrial Myocytes
During the cardiac cycle atrial myocytes are continuously exposed to shear stress (SSt), which occurs when laminar sheets of cells move relative to each other. Physiological levels of SSt can modulate activity and cellular localisation of ion channels in various cell types. However, in atrial myocytes the effects of SSt are poorly known. Here, we investigate the effect of SSt on the atrial repolarisation potassium (K+) current. Whole cell K+ currents were recorded from freshly isolated rat atrial myocytes while they were subjected to SSt of 0.5 dyne/cm2. Increasing SSt to 4.5 dyne/cm2 induced a progressive increase in K+ current from 3.8pA/pF ±0.5 to 43.2pA/pF±8.9. The effect was reversible and was inhibited by the K+ channel blocker 4-AP (100μM) at a concentration which specifically blocks Kv1.5, the channel underling the atrial repolarising current IKur. Myocytes exposed to SSt showed a shortening in action potential duration consistent with an increase in IKur. The process was intracellular calcium dependent, as it was prevented with the inclusion of BAPTA (10mM) in the patch pipette. We have previously shown that Kv1.5 can be recruited to the plasma membrane (PM) from a subcellular pool, through a Rab11 dependent process. The increase in current by SSt was attributed to increased trafficking of channels from these pools, as it was inhibited by N-ethylmaleimide, which inhibits fusion of vesicles to the PM. In addition, the SSt response was attenuated by both colchichine (10μM) which destroys the microtubule network (69.1%), and cytochalasin D (5μM) which inhibits actin polymerisation (52.1%), indicating a role for the cytoskeleton in mediating the effect. The integrin inhibitor echistatin (100nM) and the focal adhesion kinase inhibitor (FAK) FAKi14 (50μM) both prevented the SSt effect, suggesting that this integrin signalling pathway is part of the mechanotransduction mechanism. Interestingly, SSt alone was sufficient to activate FAK as shown by an increase in its phosphorylation as assayed by immunofluorescence. In conclusion, SSt induces the recruitment of Kv1.5 channels to the PM via an integrin/FAK dependent process. Thus, pools of Kv1.5 may comprise an inducible reservoir which can repolarise the atrium under conditions of mechanical stress.
- © 2012 by American Heart Association, Inc.