HCN4, Sinus Bradycardia and Atrial Fibrillation

Based on their established role in the generation of spontaneous activity in pacemaker cells and control of cardiac rate, funny/hyperpolarisation-activated, cyclic nucleotide gated 4 (HCN4) channels are natural candidates in the search for causes of sinus arrhythmias. Investigation of funny current-related inheritable arrhythmias has led to the identification of several mutations of the HCN4 gene associated with bradycardia and/or more complex arrhythmias. More recently, the search has been extended to include auxiliary proteins such as the minK-related peptide 1 (MiRP1) beta-subunit. All mutations described so far are loss-of-function and in agreement with the role of funny channels, the predominant type of arrhythmia found is bradycardia. Funny channel-linked arrhythmias, however, also include atrioventricular (AV) block and atrial fibrillation, in agreement with an emerging new concept according to which defective funny channels have a still unexplored role in impairing AV conduction and triggering atrial fibrillation. Also, importantly, recent work shows that HCN4 mutations can be associated with cardiac structural abnormalities. In this short review I briefly address the current knowledge of funny/HCN4 channel mutations and associated sinus and more complex arrhythmias.