Calcium/calmodulin-dependent serine protein kinase CASK modulates the L-type calcium current.

AIM

The L-type voltage-gated calcium channel Ca1.2 mediates the calcium influx into cells upon membrane depolarization. The list of cardiopathies associated to Ca1.2 dysfunctions highlights the importance of this channel in cardiac physiology. Calcium/calmodulin-dependent serine protein kinase (CASK), expressed in cardiac cells, has been identified as a regulator of Ca2.2 channels in neurons, but no experiments have been performed to investigate its role in Ca1.2 regulation.

METHODS AND RESULTS

Full length or the distal C-terminal truncated of the pore-forming Ca1.2 channel (Ca1.2α1c), both present in cardiac cells, were expressed in TsA-201 cells. In addition, a shRNA silencer, or scramble as negative control, of CASK was co-transfected in order to silence CASK endogenously expressed. Three days post-transfection, the barium current was increased only for the truncated form without alteration of the steady state activation and inactivation biophysical properties. The calcium current, however, was increased after CASK silencing with both types of Ca1.2α1c subunits suggesting that, in absence of calcium, the distal C-terminal counteracts the CASK effect. Biochemistry experiments did not reveals neither an alteration of Ca1.2 channel protein expression after CASK silencing nor an interaction between Ca1.2α1c subunits and CASK. Nevertheless, after CASK silencing, single calcium channel recordings have shown an increase of the voltage-gated calcium channel Ca1.2 open probability explaining the increase of the whole-cell current.

CONCLUSION

This study suggests CASK as a novel regulator of Ca1.2 via a modulation of the voltage-gated calcium channel Ca1.2 open probability.