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Abstract
HCN channels. General overview
The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel family implies four members (HCN1-4) which are expressed in the heart and the nervous system. The current flowing through HCN channels was termed as If or Ih or Iq. It was demonstrated that the heterogeneity of native Ih currents is attributable to, at least partly, the tissue-specific expression of HCN channel genes [1]. The hyperpolarization–activated current was named "funny" current (If) in the heart because of its unusual electrophysiological characteristics [2], while this current in the nervous system was designated Ih (for "hyperpolarization") or Iq (for "queer" current). If/Ih current plays a substantial role in the initiation and control of the heart rate [3]. If/Ih generates rhythmic activities particularly in thalamocortical circuits, has a function in regulating synaptic integration (e.g. in prefrontal pyramidal neurons) [4], in neuronal cells takes part in the determination of resting membrane potential [5] (Ih is inward, and the others (Kir2 and Kleak) are outward, there is dynamic equilibrium between them), probably plays an important role in olfactory information processing [6], generates and controls oscillations of the membrane potential. The increased expression level of Ihand HCN isoforms in sensory nerves indicates that they might play a prominent role in sensory function [7] (e.g. by modulating pain thresholds) and could be targets in analgesic therapy in special conditions e.g. nerve injury based neuropathic pain. Interestingly, it turned out that some volatile anaethetic agents are able to influence the operation of HCN channels, opening an other significant field in drug research. HCN isoforms have also been found in pancreatic beta-cells and kidney, where they regulate important physiological functions [8-10]. HCN channels are expressed in the retina [11]. Ivabradine is a novel heart rate-lowering antianginal agent which inhibits the pacemaker current in the heart with high selectivity. According to the BEAUTIFUL study, ivabradine can be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater [12]. A large proportion of patients suffering from heart failure die of sudden cardiac death caused by arrhythmia. It emerged from experiments analyzing the expression pattern of HCN channel isoforms in failing heart that suppressing the activity of the upregulated HCN channel subtypes can probably preclude the development of that type of arrhythmias which are triggered by abnormal pacemaker activity in the working myocardium, as it was found that both mRNA and protein levels of HCN2 and HCN4 isoforms were significantly augmented in failing ventricles [13]. Therefore, selective HCN blockers might serve as effective agents of this profile. HCN4 is the predominant isoform in undiseased human heart, and its expression is increased by disease (e.g. heart failure). The classic antiarrhythmic compounds might exert little or insignificant effect on this isoform as recently it turned out that the blocking effects of them /quinidine, disopyramide, cibenzoline, lidocaine, mexiletine, aprindine, propafenone, flecainide, propranolol, and verapamil/ on the HCN4 channel current were weak, D,L-sotalol hardly influenced the HCN4 channel current in clinical concentrations in HEK293 cells [14].
HCN channels in the heart
