Pharmacological screening of 39 NaV modulators revealed that while many compounds interact with both bacterial NaChBac and mammalian NaV1.7 channels, they exhibit distinct functional effects on channel gating.
Pharmacological profiling of bacterial and mammalian sodium channels reveals distinct gating modulations despite conserved pore block, informing organism-specific drug design.
Abstract 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.
Zhu et al. (2020) studied this question. NaV modulators (e.g., lidocaine, ambroxol, toxins) vs. Control (vehicle/baseline) was evaluated on Channel gating and peak current modulation. Pharmacological screening of 39 NaV modulators revealed that while many compounds interact with both bacterial NaChBac and mammalian NaV1.7 channels, they exhibit distinct functional effects on channel gating.