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 I_f (f for funny)^{2, 3}. At the same time, a similar current was described in neurons and in the retina, termed, respectively, I_h (h for hyperpolarization-activated) and I_q (q for queer)³. The HCN genes were independently cloned in 1998 by three groups^4-6. These currents contribute to normal pacemaking in the sinoatrial node (SAN) and atrioventricular node of the atria and purkinje fibers in the ventricle^7,8 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 I_h activation^2,13. Acetylcholine decreases the amplitude of HCN channels, and together with activation of I_KAch, slows the pacing rate of nodal cells^8,14. Extracellular Cl^– is required for production of HCN current and variations in intracellular Cl^– have been shown to modify the conductance of I_h¹⁵.

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.

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