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

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).