HCN Channels and Cardiac Pacemaking

Cardiomyocytes located in the central part of the sinoatrial node are responsible for generating the electrical rhythm of the heart since they are endowed with the fastest automaticity of the entire conduction system. The source of this automaticity is the diastolic pacemaker phase which consists of the slow depolarization that links the end of each action potential with the beginning of the next, and the funny current (“If”) is the primary contributor of this phase. Each f-channel results from the assembly of four single subunits belonging to the family of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels which includes four isoforms (HCN1–HCN4). The biophysical and modulatory properties of the f/HCN current will be presented together with some of the underlying molecular details which have been partly unraveled by the recent structural definition of the channel obtained by cryo-electron microscopy studies. The chapter will also provide an extensive review of the mutations of the HCN4 channels in humans associated with sinus arrhythmias and left ventricular noncompaction cardiomyopathy. Functional studies based on HCN transgenic and knockout mouse models confirm the importance of the If current in sustaining the pacemaker activity since its suppression affects the cardiac performance and autonomic modulation of heart rate. These studies also provide the evidence that cardiac HCN currents are required for proper cardiac development and embryo survival. Finally, the clinical relevance of HCN channels as targets of drugs aimed to selectively reduce the heart rate will be also discussed.