Voltage-gated Na+ (Na-V) channels regulate homeostasis in bacteria and control membrane
electrical excitability in mammals. Compared to their mammalian counterparts, bacterial
Na-V channels possess a simpler, fourfold symmetric structure and have facilitated
studies of the structural basis of channel gating. However, the pharmacology of bacterial
Na-V remains largely unexplored. Here we systematically screened 39 Na-V modulators
on a bacterial channel (NaChBac) and characterized a selection of compounds on NaChBac
and a mammalian channel (human Na(V)1.7). We found that while many compounds interact
with both channels, they exhibit distinct functional effects. For example, the local
anesthetics ambroxol and lidocaine block both Na(V)1.7 and NaChBac but affect activation
and inactivation of the two channels to different extents. The voltage-sensing domain
targeting toxin BDS-I increases Na(V)1.7 but decreases NaChBac peak currents. The
pore binding toxins aconitine and veratridine block peak currents of Na(V)1.7 and
shift activation (aconitine) and inactivation (veratridine) respectively. In NaChBac,
they block the peak current by binding to the pore residue F224. Nonetheless, aconitine
has no effect on activation or inactivation, while veratridine only modulates activation
of NaChBac. The conservation and divergence in the pharmacology of bacterial and mammalian
Na-V channels provide insights into the molecular basis of channel gating and will
facilitate organism-specific drug discovery.
