HCN Channel as Therapeutic Targets for Heart Failure and Pain

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play important roles both in the control of heart rate and neuronal excitability. HCN channels open on hyperpolarization voltage, permeate to potassium and sodium, and generate an inward current, which is modulated by intracellular cAMP. HCN channels have been reported to involve in various human diseases, including heart failure, pain and epilepsy with datas from mutagenesis, transgenic mice and pharmacological studies. As a result, HCN channels may offer excellent drug development opportunities for novel analgestic, bradycardic and anticonvulsant drugs. Ivabradine is the first HCN channel inhibitor being clinically approved in 2005 for the treatment of chronic stable angina pectoris and heart failure. This review will summarize the structure and function of HCN channels. Further, we will discuss recent advances concerning the identification and action mechanism of reported HCN channel inhibitors.

Modulation of Low-Voltage-Activated Inward Current Permeable to Sodium and Calcium by DARPP-32 Drives Spontaneous Firing of Insect Octopaminergic Neurosecretory Cells

“…Generation of spontaneous rhythmic activity involved special class of ionic currents occurring during the interval between spikes (Bean, 2007). Among voltage-gated ion currents underlying the neuronal pacemaker activity, the hyperpolarization-activated cyclic-nucleotide-gated cation non-selective channels, HCN1–4, (Robinson and Siegelbaum, 2003; Santoro and Baram, 2003; He et al, 2014; Cao et al, 2016), activated at subthreshold potentials play crucial roles to establish pacemaker potential.…”

Peer Review #2 of "Capsazepine prolongation of the duration of lidocaine block of sensory transmission in mice may be mediated by modulation of HCN channel currents (v0.1)"

“…HCN channel is the principal pacemaker for rhythmical regulator and determinant for resting membrane potential in nervous system and sinoatrial node for its distinct electrophysiological properties (Benarroch, 2013;Biel et al, 2009). HCN channel also plays an important role in neuropathic pain (Cao et al, 2016). Our previous study indicates that the duration of lidocaine is significantly shortened in HCN1 knockout mice (Zhou et al, 2015).…”

Inhibition of hyperpolarization‐activated cyclic nucleotide‐gated channels by β‐blocker carvedilol

“…Interestingly, the first two ion binding sites are absent in HCN1 as revealed by the cryo-EM structure, which leads to the non-selectivity property of the channel (Lee and Mackinnon, 2017). The four isoforms of HCN channels (HCN1-HCN4) differ in their voltagedependent gating properties (Biel et al, 2009;Cao et al, 2016). Among them, the HCN1 channel has the most positive V 0.5 for activation and the fastest activation kinetics, while the HCN4 channel is the slowest voltage-gated isoform (Ludwig et al, 1998;Biel et al, 2009).…”

“…Topologically, HCN channels belong to the superfamily of voltage‐gated potassium (K v ) and cyclic nucleotide‐regulated channels. Each subunit contains six transmembrane domains (S1–S6), a re‐entrant loop between the S5–S6 helices that forms the selectivity filter and pore, and a cytosolic cyclic nucleotide‐binding domain (CNBD) attached to S6 via an 80 amino acid C‐linker (Zagotta et al ., ; Xu et al ., ; Cao et al ., ). Characteristic electrophysiological properties of HCN channel include activation on hyperpolarization, conduction of both Na + and K + and inhibition by mM concentrations of external Cs + (Robinson and Siegelbaum, ; Biel et al ., ).…”