ReviewFunny channels in the control of cardiac rhythm and mode of action of selective blockers
Introduction
Cardiac pacemaking is an electrical phenomenon, based on the function of ion channel proteins expressed on the membrane of specialized cardiac myocytes, the sino-atrial node (SAN) cells of mammalian heart. “Pacemaker” cells are endowed with the property of spontaneous activity, and generate repetitive action potentials at a constantly controlled rate, thus determining the cardiac frequency and consequently the overall cardiac performance. What gives pacemaker cells this ability? Several mechanisms contribute to provide the cellular and molecular elements necessary for pacemaking to occur, but among them, the If current has a major role in providing pacemaking competence.
SAN myocytes are characterized by the presence of a “slow diastolic” phase, which at the termination of an action potential slowly depolarizes the membrane until threshold is reached for a subsequent action potential, thus generating spontaneous, repetitive activity [2]. The origin of this phase has been thoroughly investigated [3], [4], and it is now generally recognized that activation of If at the termination of an action potential is the process responsible for generation of the diastolic depolarization.
Originally described in the SAN [1], the funny current has been the object of intense investigation and its properties and function in cardiac pacemaker cells (and, in fact, in several other types of cells where funny channels are expresssed) have been described in detail [2], [5], [6], [7], [8].
In this short review I will summarize the properties of the funny current in cardiac cells and discuss therapeutic applications of the concept of pacemaker channels, specifically their potential use in the pharmacological control of heart rate. Review articles addressing more specifically the molecular correlates of native f-channels, the hyperpolarization-activated, cyclic-nucleotide gated (HCN) channels can be found elsewhere [7], [8], [9].
Section snippets
The funny current generates the diastolic depolarization phase of pacemaker potential
Diastolic depolarization, first recorded in Purkinje fibres, was originally proposed to originate from the decay of a K+ conductance, based on conductance measurements during an action potential [10] or during voltage-clamp [11]. The mechanism proposed was analogous to that predicted by the squid axon Hodgkin–Huxley [12] model of electrical activity, where after termination of an action potential the membrane hyperpolarizes beyond the resting level, and then slowly depolarizes up to the resting
The funny current mediates autonomic control of cardiac rate
The relevance of If to pacemaking does not only derive from its role in the generation of diastolic depolarization but also from its involvement in neurotransmitter-induced control of cardiac rate. Since it was first described in the SAN, If was shown to mediate the acceleratory effect of adrenaline on pacemaker rate [1]. This is caused by a shift of the voltage dependence of the current activation curve (i.e., the f-channel open probability curve) to more positive voltages induced by βAR
The dual voltage- and cAMP-dependent regulation of f-channels
Autonomic β-adrenergic and cholinergic stimuli modify the degree of activation of f-channels, hence heart rate, by increasing and decreasing, respectively, the activity of adenylate-cyclase and intracellular cAMP, which is the second messenger of If regulation [21], [22], [23], [24]. How does cAMP activate f-channels? When this was first investigated in inside-out patches of SAN cell membranes, it led to the surprising finding that cAMP activates f-channels by direct binding, rather than by
Funny channels as tools for gene/cell therapy and pharmacological control of heart rate
The generation and modulation of heart rate by the funny current are mechanisms of basic physiological significance, but they may also represent tools for interventions aimed to the control of cardiac chronotropism by gene/cell or pharmacological approaches. Molecular/cellular approaches today allow the pacemaker function of f-channels to be transferred to resting or defective spontaneously active cardiac cells, in both in vitro coltures and in vivo conditions, as a basis for the development of
Heart-rate-reducing agents and the selective block of funny channels
The existance of molecules interacting with ion flow through funny channels is known since early studies of If in the Purkinje fibres and SAN cells. Cs+ and Rb+ ions, for example, reduce inward If when applied externally [44]. These ions however block other types of channels and are not specific f-channel blockers. In the 1980's, drugs originally termed “Pure Bradycardic Agents” (PBA's) were developed based on their ability to slow heart rate specifically by depressing diastolic depolarization
Mode of f-channel block by ivabradine
A typical feature of heart rate-reducing agents is their use-dependence, according to which the effect of drug application accumulates during repetitive activity [47]. This feature results from an accumulation of If current inhibition during repetitive activation/deactivation protocols [51] and is therapeutically useful since it implies that the slowing action of these drugs will be stronger at higher heart rates, when the bradycardic effect is most valuable.
Use-dependence derives from some of
HCN channelopathies
The clinical relevance of the mechanism of pacemaker generation and rate control by f-channels has received recent support by evidence that channel mutations may affect normal cardiac rhythm. Specifically, by investigating a large Italian family we have shown that an autosomal dominant point-mutation of HCN4 in the CNBD is responsible for a familial form of sinus bradycardia [54]. The mutation affects the f-channel function by shifting the If current activation curve to more negative voltages
Conclusions
The role of If in pacemaking, and specifically the extent to which If can be considered as the main determinant of pacemaker activity, has long been debated since the original description of the funny current [2], [3], [4], [55], and more detailed accounts of this debate can be found elsewhere (see for example [56]). Today, a bulk of evidence has accumulated leaving little doubt concerning the role played by If in the generation and control of pacemaker activity. Since the cloning of HCN
Acknowledgments
This work was partly supported by Italian Ministry of University and Research FIRB and PRIN 2004 grants.
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