In quest of a sinoatrial cell model to assess the functional effects of mutations in the HCN4 funny current gene

Several loss-of-function mutations in the HCN4 gene have been associated with human sinus bradycardia. The HCN4 channel underlies the hyperpolarization-activated `funny current' (If), which plays an important role in sinoatrial node (SAN) pacemaker activity. We attempted to assess the effects of HCN4 mutations on SAN pacemaker activity through computer simulations, using the most recent comprehensive mathematical models of single SAN cells. To this end, we incorporated the experimentally identified changes in expression and kinetics of If in the Severi-DiFrancesco and Maltsev-Lakatta models of a single rabbit SAN cell. In the Severi-DiFrancesco model, 5 out of 11 mutations tested led to cessation of pacemaker activity rather than bradycardia, emphasizing the critical role of If in this model. In contrast, the decrease in pacing rate amounted to a maximum of only 5.2% for the most severe mutation in the Maltsev-Lakatta model. These results became even more distinct upon replacement of the If equations of either model by the ones that we recently derived from our experimental data on rabbit SAN cells. We conclude that the most recent comprehensive mathematical models of single SAN cells do not allow adequate investigations of the functional effects of mutations in the HCN4 funny current gene.