Cardiac Pacemaker (If) Current: Physiological and Pharmacological Properties

Mammalian sinoatrial node (SAN) cells, the natural pacemaker cells of the heart, have an action potential characterized by the presence of a special phase, the slow diastolic (pacemaker) depolarization (phase 4), which drives pacemaker activity and has therefore attracted the interest of generations of cardiac physiologists. What is the basis of the pacemaker depolarization? Here the features of the “funny” (If) current of pacemaker cells and its involvement in the generation and autonomic regulation of heart rate are briefly addressed. I also address the involvement of If in the pharmacological control of cardiac chronotropism, and how defective “funny” channels can be responsible for inherited heart rhythm disturbances. I f G O V E R N S T H E G E N E R A T I O N A N D A U T O N O M I C C O N T R O L O F H E A R T R A T E In the original report in the sinoatrial node (SAN) in 1979 (Brown et al., 1979), the “funny” If current was described as an inward current activated on hyperpolarization in the diastolic range of voltages (Figure 1). Its properties, as well as being relevant to the generation of the diastolic depolarization phase of the action potential, were shown to be apt to mediate the changes of diastolic depolarization slope, hence of the spontaneous rate, caused by ß-receptor stimulation by adrenaline. Following its early description, much work was devoted to a thorough investigation of the properties of If in relation to kinetics, ionic nature and modulation by neuromediators (DiFrancesco, 1985; DiFrancesco, 1993). These studies confirmed that the pacemaker current is an essential mechanism in the generation of diastolic depolarization and thus in the intiation of the heartbeat, but also demonstrated the fundamental role of If in mediating the control of cardiac chronotropism by both the sympathetic and parasympathetic autonomic inputs (DiFrancesco et al., 1986; DiFrancesco et al., 1989). Which is the mechanism by which If generates spontaneous activity and modulates cardiac rate? If is activated by hyperpolarization from a threshold near -40/-50 mV, as apparent in Figure 1a,b; its activation curve (i.e., the degree of current activation at steady-state, Figure 1c) shows that the current activation saturates at about -100/-100 mV, demonstrating that the If activation range overlaps that of the diastolic depolarization phase of the action potential (Figure 1a). As illustrated by plotting the fully-activated I/V relation in Figure 1c, If is inward at diastolic voltages, with a CARDIOLOGY UPDATE 2006 University of Milano, Department of Biomolecular Sciences & Biotechnology, Laboratory of Molecular Physiology & Neurobiology,