Bacterial Voltage-Gated Sodium Channels (BacNaVs) from the Soil, Sea, and Salt Lakes Enlighten Molecular Mechanisms of Electrical Signaling and Pharmacology in the Brain and Heart

Abstract

Voltage-gated sodium channels (NaVs) provide the initial electrical signal that drives action potential generation in many excitable cells of the brain, heart, and nervous system. For more than 60 years, functional studies of NaVs have occupied a central place in physiological and biophysical investigation of the molecular basis of excitability. Recently, structural studies of members of a large family of bacterial voltage-gated sodium channels (BacNaVs) prevalent in soil, marine, and salt lake environments that bear many of the core features of eukaryotic NaVs have reframed ideas for voltage-gated channel function, ion selectivity, and pharmacology. Here, we analyze the recent advances, unanswered questions, and potential of BacNaVs as templates for drug development efforts.

Unfolding of a Temperature-Sensitive Domain Controls Voltage-Gated Channel Activation

“…Bacterial voltage-gated sodium channels (BacNa V s) share the six-transmembrane VGIC superfamily architecture and bear a four-helix bundle C-terminal cytoplasmic domain (CTD) that terminates in a four-stranded coiled-coil (Irie et al, 2012; Mio et al, 2010; Payandeh and Minor, 2015; Powl et al, 2010; Shaya et al, 2014). BacNa V s display remarkably diverse voltage responses (Payandeh and Minor, 2015; Scheuer, 2014), having activation potentials, V 1/2 , that span a ~120 mV range (Scheuer, 2014), from −98 mV for Na V Ab from Arcobacter butzleri (Payandeh et al, 2012) to +27 mV for Na V Sp1 from Silicibacter pomeroyi (Shaya et al, 2014).…”

“…BacNa V s display remarkably diverse voltage responses (Payandeh and Minor, 2015; Scheuer, 2014), having activation potentials, V 1/2 , that span a ~120 mV range (Scheuer, 2014), from −98 mV for Na V Ab from Arcobacter butzleri (Payandeh et al, 2012) to +27 mV for Na V Sp1 from Silicibacter pomeroyi (Shaya et al, 2014). The structural basis for this wide voltage response range is unknown (Scheuer, 2014).…”

Voltage-Gated Sodium Channels

“…In this case, DEKA constitutes the characteristic SF ring, as illustrated in (c). Sequence alignments of the selectivity filter and surrounding pore domain in select bacterial (Na V Ab, Na V Rh, Na V Ms, NaVAe1p) and mammalian (Na V 1.1, Na V 1.4) channels; the signature SF sequence is highlighted in orange (Payandeh & Minor Jr, 2015). The initial/final configuration of the selectivity filter was confirmed to be the most energetically favorable state using FEP methods (Aqvist & Luzhkov, 2000;).…”

“…The P-loop region contains a similar α-helix, with the addition of a unique second pore-helix in an antiparallel configuration (Figure 1.a). The available structures display remarkable similarities with Cα superposition of monomer subunits comfortably under 1 Å in most cases (Payandeh & Minor Jr, 2015), and only subtle differences in the symmetry of the pore helices with respect to the pore axis (Simone Furini & Domene, 2013).…”

“…Therefore, Na V Ab is in a supposed 'pre-open' state in which the VSD is in an active state yet the cytoplasmic entrance is closed. Subtle differences in the conformational, and hence activation, state are observed throughout the available Na V VSD structures; perspectives on voltage-sensing mechanisms as a consequence of these observations are outlined in a recent review by Payandeh et al (Payandeh & Minor Jr, 2015).…”