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HCN Channels – The Pacemaker Channels

The pacemaker current is a hyperpolarization-activated, cation-selective, inward current that modulates the firing rate of cardiac and neuronal pacemaker cells1.

The ionic conductance underlying the cardiac pacemaking was identified over 20 years ago and termed If (f for funny)2, 3. At the same time, a similar current was described in neurons and in the retina, termed, respectively, Ih (h for hyperpolarization-activated) and Iq (q for queer)3. The HCN genes were independently cloned in 1998 by three groups4-6. These currents contribute to normal pacemaking in the sinoatrial node (SAN) and atrioventricular node of the atria and purkinje fibers in the ventricle7,8 and to abnormal automatic activity of cardiac myocytes under pathological conditions9.

HCN channels also mediate repetitive synchronized firing in neurons and oscillatory behavior in neuronal networks1. Pacemaker channels are encoded by the four similar genes belonging to the HCN (Hyperpolarization-activated, cyclic nucleotidegated) gene family (HCN1-HCN4) and are most homologous to the mammalian HERG K+-channels and to the KAT1 family of K+-channels1.

All three channel families (HCN, HERG, KAT1) contain a consensus cyclic nucleotide binding (CNB) domain in the C-terminus1. HCN channels contain six transmembrane helices (S1-S6), including a positively charged S4 segment which act as a voltage sensor10, an onconducting pore between the fifth and sixth transmembrane segment and a selectivity filter (GYG sequence) (see Figure 1)2,6. The four different mammalian genes display high homology. The sequence similarity is highest within the six transmembrane regions and the CNB domain (80-90%) and much lower within the N-and C-terminal regions11.

Analogous to CNG channels and K+-channels, four HCN channel subunits probably assemble to heterotetramers12. They can also be functionally expressed as homomers.2 cAMP causes cardiac pacmaker cells to increase their intrinsic rate of firing, an effect caused by a positive shift of 10mV to the positive direction, in the voltage dependence of Ih activation2,13. Acetylcholine decreases the amplitude of HCN channels, and together with activation of IKAch, slows the pacing rate of nodal cells8,14. Extracellular Cl is required for production of HCN current and variations in intracellular Cl have been shown to modify the conductance of Ih15.

All known members of the HCN channel family (HCN1-4) are expressed in the brain, whereas only HCN1, HCN2 and HCN4 are expressed in the heart (see Table 1)6,16,17. Based on in situ hybridization, the expression of HCN4 is significantly higher than these of HCN2 and HCN1 in the SAN18.

Expression of MiRP1 β subunit enhances the expression and speeds the kinetics of activation of the HCN family of channel α subunits, especially most with HCN115.

HCN was defined as the “funny” current because of several unusual features. One unusual feature is its voltage-dependence. HCN current is activated by hyperpolarizations with a threshold of approximately –40/-50mV in the SAN. The fully activated current/voltage relation reverses near –10/ -20mV in physiological solutions as a consequence of the channel mixed permeability to K+ and Na+ (higher permeability to K+ ions than to Na+ ions), a second unusual property of HCN channels19.

The activation by hyperpolarization and permeability to Na+ and K+ are critical properties with respect to the role of HCN channels in the generation of diastolic depolarization and hence of spontaneous activity. Thus, HCN channels are opened by hyperpolarization in the pacemaker range of voltages at the end of the action potential and induces the inward current, which generates the diastolic depolarization, eventually leading to the threshold for Ca2+-channel activation and action potential firing19.

Table 1. Different properties of HCN1 – 4.


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