cAMP-dependent regulation of HCN4 channels stabilizes the sinoatrial node network by controlling the transition between firing and nonfiring pacemaker cells, rather than directly mediating the chronotropic effect.
This review challenges the classical physiological theory of heart rate regulation, proposing that cAMP-dependent regulation of HCN4 maintains continuous pacemaker firing rather than mediating the autonomic chronotropic effect.
Abstract Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are the molecular correlate of the I f current and are critically involved in controlling neuronal excitability and the autonomous rhythm of the heart. The HCN4 isoform is the main HCN channel subtype expressed in the sinoatrial node (SAN), a tissue composed of specialized pacemaker cells responsible for generating the intrinsic heartbeat. More than 40 years ago, the I f current was first discovered in rabbit SAN tissue. Along with this discovery, a theory was proposed that cyclic adenosine monophosphate–dependent modulation of I f mediates heart rate regulation by the autonomic nervous system—a process called chronotropic effect. However, up to the present day, this classical theory could not be reliably validated. Recently, new concepts emerged confirming that HCN4 channels indeed play an important role in heart rate regulation. However, the cellular mechanism by which HCN4 controls heart rate turned out to be completely different than originally postulated. Here, we review the latest findings regarding the physiological role of HCN4 in the SAN. We describe a newly discovered mechanism underlying heart rate regulation by HCN4 at the tissue and single cell levels, and we discuss these observations in the context of results from previously studied HCN4 mouse models.
Hennis et al. (Fri,) conducted a review in Cardiac pacemaking and sinoatrial node function. HCN4 channel function and cAMP-dependent regulation was evaluated. cAMP-dependent regulation of HCN4 channels stabilizes the sinoatrial node network by controlling the transition between firing and nonfiring pacemaker cells, rather than directly mediating the chronotropic effect.