Shear-Stress Triggered Voltage-Gated Kv1.5 Channels Exocytosis is Altered in Overloaded Atria

Abstract

During the cardiac cycle atrial myocytes are continuously exposed to shear stress, which occurs when laminar sheets of cells move relative to each other. However, in atrial myocytes the effects of shear stress on ion channel regulation are poorly known. Here, we report that shear stress activates a large outward current, and corresponding decreased action potential duration in atrial myocytes, primarily attributable to an increase in the membrane density of the potassium channel Kv1.5. Total outward currents were reversibly increased upon shear stress from 3.8 ± 0.5 pA/pF to 43.2 ± 8.9 pA/pF, and could be blocked using 1mM 4-AP. The increase in current was due to recruitment of channels from submembranous pools to the plasma membrane, as it could be prevented by the SNARE protein inhibitor NEM, as well as with BAPTA to buffer intracellular calcium. Recruitment of EGFP-Kv1.5 could be directly observed using total internal reflection fluorescence microscopy. The mechanosensor was found to be the integrin system signalling through focal adhesion kinase, and an intact microtubule system was required. In a rat model of heart failure (HF), the integrin system was upregulated and myocytes showed an increase in basal current. Furthermore, HF myocytes had reduced Kv1.5 expression as well as a reduced response to shear stress. These data suggest that under conditions in which the integrin system is altered, the signalling pathway resulting in recruitment of Kv1.5 is overactivated leading to an increase in basal current and a reduced capacity to respond to further stimulation. We propose that pools of Kv1.5 comprise an inducible reserve which can mediate the repolarization of the atrium following mechanical stress, and that this system is disrupted when the mechanosensor is altered.