Funny Current and Cardiac Rhythm: Insights from HCN Knockout and Transgenic Mouse Models

Abstract

In the adult animal the sinoatrial node (SAN) rhythmically generates a depolarizing wave that propagates to the rest of the heart. However, the SAN is more than a simple clock; it is a clock that adjusts its pace according to the metabolic requirements of the organism. The Hyperpolarization-activated Cyclic Nucleotide-gated channels (HCN1–4) are the structural component of the funny (If) channels; in the SAN the If current is the main driving electrical force of the diastolic depolarization and the HCN4 is the most abundant isoform. The generation of HCN KO and transgenic mouse models has advanced the understanding of the role of these channels in cardiac excitability. The HCN4 KO models that were first developed allowed either global or cardiac-specific constitutive ablation of HCN4 channels, and resulted in embryonic lethality. A further progress was made with the development of three separate inducible HCN4 KO models; in one model KO was induced globally in the entire organism, in a second, ablation occurred only in HCN4-expressing cells, and finally in a third model KO was confined to cardiac cells. Unexpectedly, the three models yielded different results; similarities and differences among these models will be presented and discussed. The functional effects of HCN2 and HCN3 knockout models and transgenic HCN4 mouse models will also be discussed. In conclusion, HCN KO/transgenic models have allowed to evaluate the functional role of the If currents in intact animals as well as in single SAN cells isolated from the same animals. This opportunity is therefore unique since it allows (1) to verify the contribution of specific HCN isoforms to cardiac activity in intact animals, and (2) to compare these results to those obtained in single cell experiments. These combined studies were not possible prior to the development of KO models. Finally, these models represent critical tools to improve our understanding of the molecular basis of some inheritable arrhythmic human pathologies.

Molecular Mapping of Sinoatrial Node HCN Channel Expression in the Human Heart

“…The expression levels of HCN isoforms strongly depends on the cardiac region and varies among species 22 . As we described previously 4, 5 , the human SAN has a complex transmural 3D structure and the leading pacemaker sites are located at the center and close to the junction of the center and tail thirds of the SAN.…”

A Decreased Expression and Functionality of Muscarinic Cholinergic Receptor in Acute Chagas Myocarditis

“…I f is a mixed inward sodium-potassium current that slowly activates on hyperpolarization at voltages in the diastolic range from −60 to −40 mV; also cAMP binds directly to f-channels and increases their open state probability. The cAMP dependence is a particularly relevant physiological property, since it underlies the I f -dependent autonomic regulation of heart rate [21] [22]. Muscarinic M2/M4 receptors via Gi-induced adenylciclase inhibition decrease the level of cAMP molecules and shift the I f activation range to more negative voltages.…”

Insights into cardiac conduction system formation provided by HCN4 expression

“…The hyperpolarization-activated cation-selective nucleotide-gated channel 4 (HCN4), encodes the “funny” current, required for pacemaking function in the heart (Bucchi et al, 2012; Stieber et al, 2003). Recently, a number of mutations in HCN4 have been associated with human arrhythmias, in particular sinus bradycardia (DiFrancesco, 2013).…”