Altered Properties of Volume‐Sensitive Outwardly Rectifying Chloride Currents in Atrial Myocytes from Heart Specific ClC‐3 Knockout Mice

ClC‐3 has been proposed as a molecular candidate for the volume‐sensitive outwardly rectifying anion channels (VSOACs) in cardiac and smooth muscle cells, although recent studies on the conventional global Clcn3 knockout mouse suggested that VSOACs might be multi‐protein complexes consisting of ClC‐3 as well as other pore‐forming and auxiliary subunits. To further test this hypothesis we produced the transgenic mice with heart specific inactivation of the ClC‐3 gene. Whole‐cell patch clamp data suggest that there may be two different groups of VSOAC currents due to the heart specific knockout of the ClC‐3 protein. For one group, the VSOAC current densities in atrial myocytes induced by hypotonic cell swelling were significantly decreased, whereas in the other group, the current densities were not changed, compared to those of the wild‐type cells. However, this VSOAC current was not blocked by the intracellular dialysis of the anti‐ClC‐3 antibody (A 1‐14 Ab), with sharp contrast to the abolished VSOAC current in the wild‐type cells. Furthermore, this unusual VSOAC current was not sensitive to the widely used VSOAC blocker tamoxifen. Although further molecular evidence is required for elucidating the possible mechanisms, these preliminary electrophysiological data support the hypothesis that ClC‐3 is a molecular component of the VSOACs in mouse atrial myocytes. (NIH grants HL‐49254 and NCRR P20RR1581)