Key Points
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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are members of the voltage-gated ion channel superfamily that are dually gated by membrane hyperpolarization and cyclic nucleotides. The current produced by HCN channels is called Ih (hyperpolarization-activated current) or If (funny current).
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HCN channels have a key role in controlling cardiac pacemaker activity and are important regulators of neuronal excitability. Dysfunction of HCN channels has been implicated in arrhythmogenic diseases of the heart and several diseases of the nervous system, including pain disorders, epilepsy and ataxia.
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Ivabradine is the first HCN channel blocker that has been clinically approved. Ivabradine efficiently lowers heart rate by blocking the sinoatrial HCN4 channel, and is used for the treatment of stable angina pectoris.
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HCN1 and HCN2 channels are involved in the pathologies of inflammatory and neuropathic pain disorders. Compounds acting on these two channels are promising candidates for treating peripheral pain modalities.
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Compounds acting on HCN1 and HCN2 channels might be also valuable in other indications such as anaesthesia and the treatment of various types of epilepsies.
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The design of agents that selectively target each of the four HCN channel isoforms is an important goal for future drug development. To avoid side effects on cardiac rhythmicity, compounds targeting the central nervous system should have a low affinity for the sinoatrial HCN4 channel.
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A first series of subtype-selective HCN channel compounds has been developed based on the ivabradine backbone. Other compounds acting on HCN channels (for example, clonidine or nicotine) may serve as alternative lead structures for the development of next-generation drugs targeting HCN channels.
Abstract
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have a key role in the control of heart rate and neuronal excitability. Ivabradine is the first compound acting on HCN channels to be clinically approved for the treatment of angina pectoris. HCN channels may offer excellent opportunities for the development of novel anticonvulsant, anaesthetic and analgesic drugs. In support of this idea, some well-established drugs that act on the central nervous system — including lamotrigine, gabapentin and propofol — have been found to modulate HCN channel function. This Review gives an up-to-date summary of compounds acting on HCN channels, and discusses strategies to further explore the potential of these channels for therapeutic intervention.
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This work was supported by the German Research Foundation (the Deutsche Forschungsgemeinschaft).
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Glossary
- Pacemaker cells
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Cardiac cells that display automaticity. The primary pacemaker cells of the heart are localized in the sinoatrial node region.
- Sinoatrial node
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Tissue located in the right atrium of the heart that generates cardiac sinus rhythm.
- Diastolic depolarization
-
Slow membrane depolarization that occurs between action potentials (that is, in the diastole of the heart) in pacemaker cells of the cardiac system.
- Sinus bradycardia
-
Heart rhythm that originates from the sinus node with a resting heart rate of 60 beats per minute or less.
- Syncope
-
Partial or complete loss of consciousness, with interruption of awareness of oneself and one's surroundings. Syncope often occurs as a result of an irregular heartbeat.
- Chronotropic incompetence
-
The inability to increase heart rate commensurately with increased activity or demand.
- QT prolongation
-
The QT interval represents the time for electrical activation and inactivation of the ventricles — the lower chambers of the heart. Prolongation of the QT interval can result in the potentially lethal arrythmia known as torsades de pointes.
- Torsades de pointes
-
A form of polymorphous ventricular tachycardia that is associated with prolongation of the cardiac QT interval that can lead to sudden cardiac death.
- Inotropic effects
-
Effects pertaining to the force of muscular contractions, particularly those of the heart.
- Absence epilepsy
-
A form of childhood epilepsy that typically results from abnormal transformation of thalamocortical oscillations.
- Temporal lobe epilepsy
-
A form of epilepsy in which seizures typically involve the hippocampus and adjacent cortices. This form of epilepsy is not thought to have a strong genetic component.
- Febrile seizure syndromes
-
Seizures that take place in children at the onset of or during fever. They are the most common types of seizures in humans, and usually short and benign. However, when they are long (especially longer than 30 minutes), these seizures are associated with a high probability of the development of hippocampal epilepsy (temporal lobe epilepsy) later in life. There are both genetic and environmental contributions to febrile seizures.
- Background potassium channels
-
Potassium channels that are constitutively open or possess high basal activity (sometimes also called 'leaky channels').
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Postea, O., Biel, M. Exploring HCN channels as novel drug targets. Nat Rev Drug Discov 10, 903–914 (2011). https://doi.org/10.1038/nrd3576
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DOI: https://doi.org/10.1038/nrd3576
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