title: HCN4, Sinus Bradycardia and Atrial Fibrillation.
abstract: 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) β-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.
authors.affiliation: PaceLab, University of Milan and Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata (CIMMBA), Milan, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: DiFrancesco
keywords: AV block; HCN4 channels; arrhythmias; atrial fibrillation; bradycardia; funny current
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