Identification and characterization of a series of novel HCN channel inhibitors

Chen, Shujun; Xu, Yao; Liang, Yemei; Cao, Ying; Lv, Jin-Yan; Pang, Jianxin; Zhou, Pingzheng

doi:10.1038/s41401-018-0162-z

Cited by 9 publications

(5 citation statements)

References 40 publications

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“…Dysrhythmia and cardiac dysfunction due to autonomic disturbances may be the possible cause of SUDEP. Compound 4e can inhibit the HCN2 channel (Chen et al, 2019 ). MEL55A is a potential HCN1/2 blocker but it increases seizure susceptibility (Kharouf et al, 2020b ).…”

Section: Resultsmentioning

confidence: 99%

The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

Kessi

Peng

Duan

et al. 2022

Front. Mol. Neurosci.

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BackgroundHyperpolarization-activated cyclic nucleotide-gated (HCN) current reduces dendritic summation, suppresses dendritic calcium spikes, and enables inhibitory GABA-mediated postsynaptic potentials, thereby suppressing epilepsy. However, it is unclear whether increased HCN current can produce epilepsy. We hypothesized that gain-of-function (GOF) and loss-of-function (LOF) variants of HCN channel genes may cause epilepsy.ObjectivesThis systematic review aims to summarize the role of HCN channelopathies in epilepsy, update genetic findings in patients, create genotype–phenotype correlations, and discuss animal models, GOF and LOF mechanisms, and potential treatment targets.MethodsThe review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, for all years until August 2021.ResultsWe identified pathogenic variants of HCN1 (n = 24), HCN2 (n = 8), HCN3 (n = 2), and HCN4 (n = 6) that were associated with epilepsy in 74 cases (43 HCN1, 20 HCN2, 2 HCN3, and 9 HCN4). Epilepsy was associated with GOF and LOF variants, and the mechanisms were indeterminate. Less than half of the cases became seizure-free and some developed drug-resistant epilepsy. Of the 74 cases, 12 (16.2%) died, comprising HCN1 (n = 4), HCN2 (n = 2), HCN3 (n = 2), and HCN4 (n = 4). Of the deceased cases, 10 (83%) had a sudden unexpected death in epilepsy (SUDEP) and 2 (16.7%) due to cardiopulmonary failure. SUDEP affected more adults (n = 10) than children (n = 2). HCN1 variants p.M234R, p.C329S, p.V414M, p.M153I, and p.M305L, as well as HCN2 variants p.S632W and delPPP (p.719–721), were associated with different phenotypes. HCN1 p.L157V and HCN4 p.R550C were associated with genetic generalized epilepsy. There are several HCN animal models, pharmacological targets, and modulators, but precise drugs have not been developed. Currently, there are no HCN channel openers.ConclusionWe recommend clinicians to include HCN genes in epilepsy gene panels. Researchers should explore the possible underlying mechanisms for GOF and LOF variants by identifying the specific neuronal subtypes and neuroanatomical locations of each identified pathogenic variant. Researchers should identify specific HCN channel openers and blockers with high binding affinity. Such information will give clarity to the involvement of HCN channelopathies in epilepsy and provide the opportunity to develop targeted treatments.

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Section: Resultsmentioning

confidence: 99%

The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

Kessi

Peng

Duan

et al. 2022

Front. Mol. Neurosci.

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“…A recent study has claimed that they discovered a new HCN2 specific drug with a completely different structure than the current HCN blockers. This study may provide a new strategy for designing and developing isoform-specific HCN channel inhibitors [48]. Thus, new drug development is the other option for future research.…”

Section: The Analgesic Effect Of Ivabradine Still Requires Further Rementioning

confidence: 94%

Pacemaking Activity in the Peripheral Nervous System: Physiology and Roles of Hyperpolarization Activated and Cyclic Nucleotide-Gated Channels in Neuropathic Pain

Liu

Wuni

Bahuva

et al. 2020

Cureus

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The most famous pacemaking activity found in the human body is in the cardiac system. However, pacemaking is also widely present in the nervous system. The ion channels responsible for the pacemaking activity are called hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels. HCN channels are activated during hyperpolarization and create an inward current named I h containing mixed sodium and potassium ions. The molecular mechanism of these unique features remains mysterious. In the peripheral nervous system (PNS), pacemaking is unique because it is only present in pathologic states when nerve damage occurs and leads to neuropathic pain. For this reason, pacemaking in neuropathic pain is also known as ectopic discharge. In our literature review, the HCN channel physiology is one of the research interests. We will present studies exploring the molecular mechanisms involved in HCN gating and ion permeability. The second research question is, what makes the pacemaking activity unique in the PNS? Thus, our paper will include studies that discuss the role of HCN channels in neuropathic pain. Given the fundamental role of HCN channels in regulating neuronal cells' discharge activity, the modulation of their function for therapeutic purposes could be useful in various pathological conditions. Here we review the present knowledge of the efficacy of HCN blocker treating neuropathic pain in humans.

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“…Because the expression profiles of the 4 HCN channel isoforms vary between different tissues and cell types, there is ongoing work to identify subtype-specific compounds as potential drug candidates. [250][251][252][253][254] For example, a series of brain-penetrant HCN1-specific inhibitors have recently been identified that enhance working memory while lacking cardiovascular side effects, qualifying them as possible candidates for the treatment of cognitive dysfunction in brain disorders. 255 Moreover, there is ongoing research on peptides based on TRIP8b, an auxiliary subunit that regulates surface expression and modulates the cAMP sensitivity of HCN channels in the brain.…”

Section: Hcn Channels In Disease and Therapymentioning

confidence: 99%

Pacemaker Channels and the Chronotropic Response in Health and Disease

Hennis,

Piantoni,

Biel

et al. 2024

Circulation Research

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Loss or dysregulation of the normally precise control of heart rate via the autonomic nervous system plays a critical role during the development and progression of cardiovascular disease—including ischemic heart disease, heart failure, and arrhythmias. While the clinical significance of regulating changes in heart rate, known as the chronotropic effect, is undeniable, the mechanisms controlling these changes remain not fully understood. Heart rate acceleration and deceleration are mediated by increasing or decreasing the spontaneous firing rate of pacemaker cells in the sinoatrial node. During the transition from rest to activity, sympathetic neurons stimulate these cells by activating β-adrenergic receptors and increasing intracellular cyclic adenosine monophosphate. The same signal transduction pathway is targeted by positive chronotropic drugs such as norepinephrine and dobutamine, which are used in the treatment of cardiogenic shock and severe heart failure. The cyclic adenosine monophosphate–sensitive hyperpolarization–activated current (I f ) in pacemaker cells is passed by hyperpolarization-activated cyclic nucleotide-gated cation channels and is critical for generating the autonomous heartbeat. In addition, this current has been suggested to play a central role in the chronotropic effect. Recent studies demonstrate that cyclic adenosine monophosphate–dependent regulation of HCN4 (hyperpolarization-activated cyclic nucleotide-gated cation channel isoform 4) acts to stabilize the heart rate, particularly during rapid rate transitions induced by the autonomic nervous system. The mechanism is based on creating a balance between firing and recently discovered nonfiring pacemaker cells in the sinoatrial node. In this way, hyperpolarization-activated cyclic nucleotide-gated cation channels may protect the heart from sinoatrial node dysfunction, secondary arrhythmia of the atria, and potentially fatal tachyarrhythmia of the ventricles. Here, we review the latest findings on sinoatrial node automaticity and discuss the physiological and pathophysiological role of HCN pacemaker channels in the chronotropic response and beyond.

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Identification and characterization of a series of novel HCN channel inhibitors

Cited by 9 publications

References 40 publications

The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

Pacemaking Activity in the Peripheral Nervous System: Physiology and Roles of Hyperpolarization Activated and Cyclic Nucleotide-Gated Channels in Neuropathic Pain

Pacemaker Channels and the Chronotropic Response in Health and Disease

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