Abstract
Entry and extrusion of cations are essential processes in living cells. In alkaliphilic prokaryotes, high external pH activates voltage-gated sodium channels (Nav), which allows Na(+) to enter and be used as substrate for cation/proton antiporters responsible for cytoplasmic pH homeostasis. Here, we describe a new member of the prokaryotic voltage-gated Na(+) channel family (NsvBa; <underline>N</underline>on-<underline>s</underline>elective <underline>v</underline>oltage-gated, <underline>B</underline>acillus <underline>a</underline>lcalophilus) that is nonselective among Na(+), Ca(2+) and K(+) ions. Mutations in NsvBa can convert the nonselective filter into one that discriminates for Na(+) or divalent cations. Gain-of-function experiments demonstrate the portability of ion selectivity with filter mutations to other Bacillus Nav channels. Increasing pH and temperature shifts their activation threshold towards their native resting membrane potential. Furthermore, we find drugs that target Bacillus Nav channels also block the growth of the bacteria. This work identifies some of the adaptations to achieve ion discrimination and gating in Bacillus Nav channels.
Highlights
Ion selectivity is a defining feature of ion channels
We find that a combination of higher temperature and pH are required to reduce the activation threshold of channel opening in Bacillus Nav channels, which is unique to this family of sodium channels
Among the first alkaliphilic extremophiles described in the literature, the gram-positive, rod-shaped Bacillus alcalophilus AV was initially isolated from human feces (Vedder, 1934)
Summary
While the structural and biophysical determinants of K+ selectivity are well described (Doyle et al, 1998; Jiang et al, 2003), those of Na+ and Ca2+ are unresolved. To fill this knowledge gap, the voltage-gated sodium channels (Nav channels) from bacteria have been extensively studied by structural biologists. The molecular arrangement that enables Na+-selectivity in prokaryotes might differ from mammalian voltagegated Na+ channels. It is not clear if structural features that determine ion selectivity in homotetrameric prokaryotic NaV reflect the functionally heterotetrameric eukaryotic sodium channels
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