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

Abstract

The hyperpolarization-activated cation current (Ih) exhibits a slowly activating time course of the current (Ih) 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 Ih magnitude. Carisbamate, an anticonvulsant agent, not only inhibited the Ih amplitude but also reduced the strength of voltage-dependent hysteresis (Hys(V)) associated with Ih. Cilobradine, similar to ivabradine, inhibited the amplitude of Ih; however, it also suppressed the amplitude of delayed-rectifier K+ currents. Dexmedetomidine, an agonist of α2-adrenergic receptor, exerted a depressant action on Ih in a concentration-dependent fashion. Suppression of Ih 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 Ih amplitude as well as to depress Hys(V)’s strength of Ih. Pirfenidone, a pyridine derivative known to be an anti-fibrotic agent, depressed the Ih magnitude in a concentration- and voltage-dependent fashion. Tramadol, a synthetic centrally active analgesic, was shown to reduce the Ih 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 Ih. Conversely, oxaliplatin, a platinum-based chemotherapeutic compound, was observed to effectively increase the Ih amplitude. Collectively, the regulatory effects of these compounds or herbal drugs on cellular function can be partly attributed to their perturbations on Ih.

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“…Additionally, a deeper understanding of dexmedetomidine's interaction with HCN channels may offer new insights into managing various pain conditions that involve modulation of neuronal excitability. 29,30 There are still some limitations in the current study. While forskolin has been extensively employed as an enhancer of HCN channels through the elevation of cyclic AMP levels, it is noteworthy that cAMP, a second messenger, may elicit additional effects.…”

Assessing the Impact of Agents with Antiviral Activities on Transmembrane Ionic Currents: Exploring Possible Unintended Actions

“…In recent research conducted on pituitary GH 3 cells, it was demonstrated that exposure to CBD leads to the suppression in the amplitudes of I K(M) and the hyperpolarization-activated cation current (I h ), with the corresponding IC 50 values of 3.6 and 3.3 µM, respectively [14]. The biophysical property of I h is distinctive, marked by its slow activation kinetics during sustained hyperpolarization [38,39]. Furthermore, given CBD's impact on ion channels situated on the cell membrane, it appears unlikely that these effects can be solely ascribed to CBD's interaction with cannabinoid receptors.…”