Up-regulation of voltage-gated sodium channels by peptides mimicking S4-S5 linkers reveals a variation of the ligand-receptor mechanism

Olfat Malak (1) , Fayal Abderemane-Ali (1) , Yue Wei (1) , Fabien C Coyan (1) , Gilyane Pontus (1) , David Shaya (2) , Céline Marionneau (1) , Gildas Loussouarn (1)

1 ITX - ITX - unité de recherche de l'institut du thorax
2 UC San Francisco - University of California [San Francisco]

Prokaryotic NaV channels are tetramers and eukaryotic NaV channels consist of a single subunit containing four domains. Each monomer/domain contains six transmembrane segments (S1-S6), S1-S4 being the voltage-sensor domain and S5-S6 the pore domain. A crystal structure of NaVMs, a prokaryotic NaV channel, suggests that the S4-S5 linker (S4-S5L) interacts with the C-terminus of S6 (S6T) to stabilize the gate in the open state. However, in several voltage-gated potassium channels, using specific S4-S5L-mimicking peptides, we previously demonstrated that S4-S5L/S6T interaction stabilizes the gate in the closed state. Here, we used the same strategy on another prokaryotic NaV channel, NaVSp1, to test whether equivalent peptides stabilize the channel in the open or closed state. A NaVSp1-specific S4-S5L peptide, containing the residues supposed to interact with S6T according to the NaVMs structure, induced both an increase in NaVSp1 current density and a negative shift in the activation curve, consistent with S4-S5L stabilizing the open state. Using this approach on a human NaV channel, hNaV1.4, and testing 12 hNaV1.4 S4-S5L peptides, we identified four activating S4-S5L peptides. These results suggest that, in eukaryotic NaV channels, the S4-S5L of DI, DII and DIII domains allosterically modulate the activation gate and stabilize its open state.

Domaines: Biochimie, Biologie Moléculaire

Olfat Malak, Fayal Abderemane-Ali, Yue Wei, Fabien C Coyan, Gilyane Pontus, et al.. Up-regulation of voltage-gated sodium channels by peptides mimicking S4-S5 linkers reveals a variation of the ligand-receptor mechanism. Scientific Reports, 2020, 10, pp.5852. ⟨10.1038/s41598-020-62615-6⟩. ⟨hal-02531094⟩