Modulating Hyperpolarization-Activated Cation Currents through Small Molecule Perturbations: Magnitude and Gating Control

Cheng-Shih Chen; Edmund Cheung So; Sheng-Nan Wu

doi:10.3390/biomedicines11082177

Modulating Hyperpolarization-Activated Cation Currents through Small Molecule Perturbations: Magnitude and Gating Control

Biomedicines. 2023 Aug 2;11(8):2177. doi: 10.3390/biomedicines11082177.

Authors

Cheng-Shih Chen¹, Edmund Cheung So¹, Sheng-Nan Wu^{2

3

4}

Affiliations

¹ Department of Anesthesia, An Nan Hospital, China Medical University, Tainan 70965, Taiwan.
² School of Medicine, National Sun Yat Sen University College of Medicine, Kaohsiung 804, Taiwan.
³ Department of Medical Education & Research, An Nan Hospital, China Medical University, Tainan 70965, Taiwan.
⁴ Department of Physiology, National Cheng Kung University Medical College, Tainan 701, Taiwan.

Abstract

The hyperpolarization-activated cation current (I_h) exhibits a slowly activating time course of the current (I_h) when the cell membrane is hyperpolarized for an extended duration. It is involved in generating electrical activity in various excitable cells. Numerous structurally distinct compounds or herbal drugs have the potential to impact both the magnitude and gating kinetics of this current. Brivaracetam, a chemical analog of levetiracetam known to be a ligand for synaptic vesicle protein 2A, could directly suppress the I_h magnitude. Carisbamate, an anticonvulsant agent, not only inhibited the I_h amplitude but also reduced the strength of voltage-dependent hysteresis (Hys_(V)) associated with I_h. Cilobradine, similar to ivabradine, inhibited the amplitude of I_h; however, it also suppressed the amplitude of delayed-rectifier K⁺ currents. Dexmedetomidine, an agonist of α2-adrenergic receptor, exerted a depressant action on I_h in a concentration-dependent fashion. Suppression of I_h amplitude was observed when GAL-021, a breathing control modulator, was present at a concentration exceeding 30 μM. Lutein, one of the few xanthophyll carotenoids, was able to suppress the I_h amplitude as well as to depress Hys_(V)'s strength of I_h. Pirfenidone, a pyridine derivative known to be an anti-fibrotic agent, depressed the I_h magnitude in a concentration- and voltage-dependent fashion. Tramadol, a synthetic centrally active analgesic, was shown to reduce the I_h magnitude, independent of its interaction with opioid receptors. Various herbal drugs, including ent-kaurane-type diterpenoids from Croton tonkinensis, Ganoderma triterpenoids, honokiol, and pterostilbene, demonstrated efficacy in reducing the magnitude of I_h. Conversely, oxaliplatin, a platinum-based chemotherapeutic compound, was observed to effectively increase the I_h amplitude. Collectively, the regulatory effects of these compounds or herbal drugs on cellular function can be partly attributed to their perturbations on I_h.

Keywords: current kinetics; herbal drugs; hyperpolarization-activated cation current; small molecules.

Publication types

Review

Abstract

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