Engineering analysis of cardiac electrical activity in response to calmodulin mutations

Calmodulin (CaM) is a ubiquitous protein involved in different aspects of Ca²⁺ sensing and regulation in cardiac cells. One of its established roles is in the Ca²⁺-dependent inactivation of L-type voltage-gated Ca²⁺ channels. This study examined how mutations in CaM affect action potential duration (APD) in rat neonatal ventricular myocytes, organized in confluent monolayers. Analysis was performed on optically obtained transmembrane potentials in monolayers infected with viral constructs of 4 different CaM mutants. The mean values for 50% and 80% APD (APD₅₀ and APD₈₀) for the treated groups were compared to a control group. The results showed statistically significant APD₅₀ and APD₈₀ prolongations for CaM mutations involving the carboxy-terminus. The most dramatic response resulted in over 200% increase in APD. The experimental data were compared to computer modeling data, using the Luo-Rudy cell model to simulate cardiac cells under various conditions, assuming that the major effects concern Ca²⁺-dependent inactivation of L-type channels. The model results, where the most dramatic prolongation was only 27%, did not match the experimental data quantitatively. This study suggests a more profound and complex role for CaM in APD regulation than previously thought.