The role of resistance to inhibitors of cholinesterase 8b in the control of heart rate.

We have assessed the role of ric-b8 in the control of heart rate after the gene was implicated in a recent genome wide association study in resting heart rate. We developed a novel murine model in which it was possible to conditionally delete ric-8b in the SA node after the addition of tamoxifen. Despite this we were unable to obtain homozygotes and thus studied heterozygotes. Haplo-insufficiency of ric-8b in the sinoatrial node induced by the addition of tamoxifen in adult animals leads to mice with a reduced heart rate. However other electrocardiographic intervals (e.g. PR, QRS) were normal and there was no apparent arrhythmia such as heart block. The positive chronotropic response to isoprenaline was abrogated, while the response to carbachol was unchanged. The pacemaker current If (funny current) has an important role in regulating heart rate and its' function is modulated by both isoprenaline and carbachol. Using a heterologous system expressing HCN4, we show that ric-8b can modulate the HCN4 current. Overexpression of ric-8b led to larger HCN4 currents while silencing ric-8b led to smaller currents. Ric-8b modulates heart rate responses in-vivo likely via its actions on the stimulatory G-protein.