Review
Serious workings of the funny current

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Abstract

Since its first description in 1979 (Brown et al., 1979. Nature 280, 235–236), extensive work on the If current has amply demonstrated its role in the generation and neurotransmitter-induced modulation of pacemaker activity in heart (DiFrancesco, 1993. Annual Review of Physiology 55, 455–472). At pacemaker voltages, If is an inward current activated by negative voltage and by intracellular cAMP. Moderate β-receptor stimulation accelerates, and vagal stimulation slows, cardiac rate by increasing and decreasing, respectively, If at diastolic potentials via changes in cAMP level. Cloning of four isoforms of hyperpolarization-activated, cyclic-nucleotide-gated (HCN) channels in the late 1990s has shown their correlation to native f-channels. Comparison of the properties of native pacemaker channels with those of HCN channels has provided information concerning the composition and molecular features of native channels in different cardiac regions. The relevance of If to pacemaker generation and modulation makes f-channels a natural target of drugs aiming to control pharmacologically heart rate. Agents selectively reducing heart rate have been developed which act by specific inhibition of If, such as ivabradine; these drugs have a high potential for treatment of diseases where heart rate reduction is beneficial, such as angina and heart failure. Knowledge of the molecular properties of HCN clones will help the development of drugs specifically interacting with cardiac, rather than neuronal pacemaker channels. Devices able to replace electronic pacemakers and based on the delivery of a cellular source of pacemaker channels to non-pacing tissue (biological pacemakers) are likely to be developed in the near future for use in therapies for diseases of heart rhythm.

Introduction

Sino-atrial node (SAN) cells pace the heart by their ability to generate spontaneous action potentials, based on the presence of a special phase (phase 4) of the action potential, the diastolic (or pacemaker) depolarization. Upon termination of an action potential, the pacemaker depolarization slowly depolarizes the membrane up to the threshold for a new action potential, thus inducing repetitive activity.

The first description in 1979 (Brown et al., 1979) of an inward current activated on hyperpolarization in the pacemaker range of voltages in SAN preparations showed for the first time the existance of a mechanism able to generate spontaneous activity, and to modify its rate in the presence of β-adrenergic input.

The “pacemaker” current in the SAN was termed “funny” (If current) because of its atypical property of being an inward current slowly activating on hyperpolarization at voltages comprising the diastolic depolarization. Other atypical properties found subsequently included a dual gating by voltage and internal cAMP, which binds directly to channel proteins and acts as a second messenger, and a very small single-channel conductance, apparently in contrast with a permeability that selects poorly between Na+ and K+ ions.

Since its early description, the funny current was the object of intense investigation in cardiac and non-cardiac preparations (where it was named Ih).

An important breakthrough in the knowledge of the molecular aspects underlying the properties of the funny current was accomplished in the late 1990s by the cloning of the hyperpolarization-activated, cyclic-nucleotide-gated (HCN) family of channels, which represent the moleculal building blocks of native f/h-channels. This has allowed a detailed search for the elements responsible for the kinetic, ionic and modulatory properties of the pacemaker current.

Here I will briefly review the major steps in the understanding of the properties of the funny current and its role in the generation and modulation of pacemaker activity. Also, how the features of pacemaker channels can be used as the basis for pharmacological and biomedical therapy of heart rate control will be discussed.

Section snippets

Relevance of the funny current to pacemaking: generation of pacemaker activity

In SAN myocytes, If activation during the last fraction of action potential repolarization is the process mainly responsible for generation of the diastolic depolarization and spontaneous activity.

Relevance of If has been disputed in the past (Irisawa et al., 1993). Among the various hypothesis proposed as alternatives to the If-based pacemaker mechanism, one assumed that the diastolic depolarization rate was under control of a decaying K+ current, which acted in the background of a

Relevance of the funny current to pacemaking: modulation by autonomic transmitters

As well as contributing essentially to generation of spontaneous activity, If also mediates the chronotropic action of neurotransmitters, a mechanism that further underlines its role in pacemaking. Sympathetic stimulation shifts the If activation curve to more positive voltages, thus providing more inward current and steepening the slope of diastolic depolarization. The positive shift of If activation curve is due to increased cAMP levels operated by βAR-induced activation of adenylate-cyclase.

How many pacemaker mechanisms in the heart?

Several depolarizing currents have been proposed to play a role in the generation of diastolic depolarization along with If, such as background Na+ current, sustained Na+-dependent inward current and others (Irisawa et al., 1993; Zhang et al., 2000), but a crucial involvement under normal conditions still awaits confirmation. Substantial evidence, on the other hand, has been collected suggesting that sarcoplasmic reticulum (SR) Ca2+-transients affect heart rate (Lipsius et al., 2001). For

Not so funny any more: cloning of the pacemaker channel

Cloning of the HCN family of channels in the late 1990s (Clapham, 1998) has given a strong impulse to the search for the molecular basis of f-channel properties. The first member of this family was cloned by chance from mouse brain (Santoro et al., 1997, Santoro et al., 1998), and other members of the family were cloned soon after in mammalian tissue (HCN1-4) (Ludwig et al., 1998, Ludwig et al., 1999; Vaccari et al., 1999; Ishii et al., 1999; Seifert et al., 1999).

HCN channels belong to the

If as a tool to control heart rate: heart rate-reducing agents

The finding that If controls heart rate impacts on our basic understanding of the physiological mechanisms underlying cardiac function, but it also provides a clue as to possible ways to affect heart rate, and consequently heart function, by pharmacological or other means. For example, a strict correlation exists between reduction of If as obtained by blockade of If channels and the slowing of spontaneous activity of pacemaker cells. Typically, molecules which selectively block f-channels such

Conclusions

A quarter of a century after its finding, the “funny” current has been described in detail in cardiac and neuronal preparations, and its role has been amply demonstrated in a variety of cellular functions. In the heart, If generates spontaneous activity and mediates the control of cardiac rate by autonomic neurotransmitters. f-channels are the natural target of drugs aiming to control pharmacologically heart rate, such as ivabradine, a selective heart rate-reducing agent, which has the

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