The Funny Current in Cardiac Non-Pacemaker Cells: Functional Role and Pharmacological Modulation

Abstract

In mammalians, heart rhythm originates in the sinoatrial node, a specialized region of the right atrium with defined anatomical and functional properties. The sinoatrial node acts as primary pacemaker in the heart owing to its unique ability to generate spontaneous action potentials at a rate faster than subsidiary pacemakers (the atrioventricular node and Purkinje fibers) (Vassalle, 1977). Propagation of action potentials from the sinoatrial node is first directed to the atria and then to the ventricles through a specialized conduction system that drives and coordinates the rhythmic contraction of heart chambers (Figure 1). The pacemaker function of the sinoatrial node derives from a key electrogenic property, the diastolic depolarization phase or pacemaker phase of the action potential. It is a slow, positive increase in voltage across the cell membrane occurring between the end of one action potential and the beginning of the next; it causes the cell membrane to reach the threshold potential required to generate a subsequent action potential (DiFrancesco, 1991; DiFrancesco, 2010). The diastolic depolarization phase is absent in normal atrial and ventricular myocytes that rest at stable membrane potential values at the termination of the action potential. Investigations aimed at elucidating the ionic mechanisms of pacemaking have proposed different candidates as major contributors responsible for the generation of the diastolic depolarization phase. At present, despite the issue is still a matter of debate, a wealth of information clearly agrees that two major mechanisms, membrane-associated ion currents and calcium release from sarcoplasmic reticulum, contribute to form a coordinated system that drives automaticity of normal cardiac pacemaker cells (Lakatta et al., 2010). Among the membrane associated currents, the hyperpolarization-activated current or funny current (If ) is considered a major player in both generation of cardiac spontaneous activity and rate control (DiFrancesco, 1991; DiFrancesco, 2010). If is an inward mixed-cation current carried by potassium and sodium, slowly activating on hyperpolarization at voltages comprising the diastolic depolarization phase of sinoatrial node cells (−40/−60 mV); for these reasons it was termed funny current. Accordingly, several loss-of-function mutations (DiFrancesco, 2010), as well as the down-regulation of constitutive subunits of f-channel in pacemaker cells (Zicha et al., 2005) have been demonstrated to cause sinus node dysfunction and rhythm disturbances.