The Bis(1,2,3,4-tetrahydroisoquinoline) Alkaloids Cepharanthine and Berbamine Are Ligands of SK Channels.

Cepharanthine, a multitarget alkaloid which has recently been shown to be effective against SARS-Cov-2, and berbamine, an alkaloid characterized as a calcium channel blocker, both share key structural elements with known small conductance calcium-activated potassium (SK) channel blockers. These structural similarities led us to evaluate their affinity for SK channels. Therefore, we performed in vitro binding on SK2 and SK3 subtypes and highlighted micromolar to sub-micromolar affinities. Respectively, the Ki values on SK2 and SK3 are 1,318 µM and 1,091 µM for cepharanthine and 0,284 µM and 0,679 µM for berbamine. These newfound affinities correspond to the concentrations at which the alkaloids are found to be active against several pathologies. As SK interactions occur at the same levels as their therapeutic effects, there is a strong incentive to further investigate whether SK channels are involved in their pharmaceutical potency.

The gating pore blocker 1-(2,4-xylyl)guanidinium selectively inhibits pacemaking of midbrain dopaminergic neurons.

Although several ionic mechanisms are known to control rate and regularity of the slow pacemaker in dopamine (DA) neurons, the core mechanism of pacing is controversial. Here we tested the hypothesis that pacemaking of SNc DA neurons is enabled by an unconventional conductance. We found that 1-(2,4-xylyl)guanidinium (XG), an established blocker of gating pore currents, selectively inhibits pacemaking of DA neurons. The compound inhibited all slow pacemaking DA neurons that were tested, both in the substantia nigra pars compacta, and in the ventral tegmental area. Interestingly, bursting behavior was not affected by XG. Furthermore, the drug did not affect fast pacemaking of GABAergic neurons from substantia nigra pars reticulata neurons or slow pacemaking of noradrenergic neurons. In DA neurons, current-clamp analysis revealed that XG did not appear to affect ion channels involved in the action potential. Its inhibitory effect persisted during blockade of all ion channels previously suggested to contribute to pacemaking. RNA sequencing and voltage-clamp recordings yielded no evidence for a gating pore current to underlie the conductance. However, we could isolate a small subthreshold XG-sensitive current, which was carried by both Na+ and Cl- ions. Although the molecular target of XG remains to be defined, these observations represent a step towards understanding pacemaking in DA neurons.