Resting-State Structure and Gating Mechanism of a Voltage-Gated Sodium Channel

Wisedchaisri, Goragot; Tonggu, Lige; McCord, E.; El-Din, Tamer M. Gamal; Wang, Liguo; Zheng, Ning; Catterall, William A.

doi:10.1016/j.cell.2019.06.031

Cited by 160 publications

(249 citation statements)

References 83 publications

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“…11a and ligand-receptor in Fig. 11b) may coexist: the interaction between S4-S5 L and S6 T suggested in the closed state (recent work of Wisedchaisri et al on the bacterial channel Na V Ab 19 ) may completely reconfigure in the open state (studies on NavMs 8,16,17 , and also the present study on Na V Sp1 and Na V 1.4). Interestingly, S4-S5 L residues implicated in the interaction with S6 T in the Na V Ab closed state (highlighted in Supplemental Fig.…”

Section: Discussionsupporting

confidence: 51%

“…the activation gate is closed. Upon membrane depolarization, constriction is relieved, and channel activation gate can open 10,12,15,[19][20][21] . On the other hand, other studies performed on the bacterial Na V Ms (from Magnetococcus marinus) channel suggest that the S4-S5 L may also be involved in an interaction motif stabilizing the channel open state 8,16,17 .…”

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confidence: 99%

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

Malak

Abderemane-Ali

Wei

et al. 2020

Sci Rep

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prokaryotic na V channels are tetramers and eukaryotic na V 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 Na V Ms, a prokaryotic na V channel, suggests that the S4-S5 linker (S4-S5 L) interacts with the C-terminus of S6 (S6 t) to stabilize the gate in the open state. However, in several voltage-gated potassium channels, using specific S4-S5 L-mimicking peptides, we previously demonstrated that S4-S5 L /S6 t interaction stabilizes the gate in the closed state. Here, we used the same strategy on another prokaryotic Na V channel, Na V Sp1, to test whether equivalent peptides stabilize the channel in the open or closed state. A na V Sp1-specific S4-S5 L peptide, containing the residues supposed to interact with S6 t according to the na V Ms structure, induced both an increase in Na V Sp1 current density and a negative shift in the activation curve, consistent with S4-S5 L stabilizing the open state. Using this approach on a human na V channel, hNa V 1.4, and testing 12 hNa V 1.4 S4-S5 L peptides, we identified four activating S4-S5 L peptides. These results suggest that, in eukaryotic Na V channels, the S4-S5 L of DI, DII and DIII domains allosterically modulate the activation gate and stabilize its open state. Voltage-gated sodium channels (Na V) are crucial in excitable as well as non-excitable cells and mutations in Na V 1.x-subunits have been associated with muscular, neuronal and cardiac channelopathies in human 1. Voltage-gated potassium (K V) channels and prokaryotic Na V channels are tetramers of subunits containing six transmembrane segments (S1 to S6). Each of the four subunits consists of one voltage-sensor domain (S1 to S4) and a pore domain (S5-S6). The four pore domains tetramerize to form a single pore module, which is regulated by the four voltage sensor domains. The arrangement of eukaryotic Na V channels is similar, with one major difference: the channel is made of a single subunit containing four homologous domains, rather than four identical subunits. Each domain in eukaryotic Na V channels is structurally equivalent to one subunit in K V or prokaryotic Na V channels, and consists of six transmembrane segments (S1 to S6). Despite intensive work on the voltage-gating of K V and Na V channels, we still lack a clear picture describing the coupling between S4 voltage-sensor movement and S6 pore gating. Both structural and functional studies identified the linker between S4 and S5 (named S4-S5 L) and the C-terminus of S6 (named S6 T), as major actors in this coupling 2-21. Different coupling mechanisms have been suggested. The crystal structure of K V 1.2, and more recently the cryo-electron microscopy and crystal structures of both eukaryotic and prokaryotic Na V channels suggested that the four S4-S5 L form a mechanical lever or a constriction ring intimately interacting with S6 T when

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Section: Discussionsupporting

confidence: 51%

mentioning

confidence: 99%

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

Malak

Abderemane-Ali

Wei

et al. 2020

Sci Rep

View full text Add to dashboard Cite

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“…Importantly, Kv1.2/2.1 and Na V Ab structures showed the S4 segment in nearly identical positions (Long et al, 2007;Payandeh et al, 2011), confirming the vertical position of the S4 segment in the activated state. Countercharge to S4 arginine residue interactions have been revealed with crystallographic data from Na V Ab, Na V Rh, and Na V Ms (Payandeh et al, 2011;Payandeh et al, 2012;Zhang et al, 2012;Sula et al, 2017;Wisedchaisri et al, 2019). It has also been hypothesized that negatively charged residues tune the hydrophilicity of the inner and outer vestibules of the VSD (Palovcak et al, 2014), while the central, hydrophobic region separates these vestibules and focuses the electric field (Starace and Bezanilla, 2004;Ahern and Horn, 2005;Chanda and Bezanilla, 2008;Lacroix et al, 2014).…”

Section: Structural Studies Illuminate Voltage Sensor Topology and Elmentioning

confidence: 97%

Roles for Countercharge in the Voltage Sensor Domain of Ion Channels

Groome

Bayless-Edwards

2020

Front. Pharmacol.

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Voltage-gated ion channels share a common structure typified by peripheral, voltage sensor domains. Their S4 segments respond to alteration in membrane potential with translocation coupled to ion permeation through a central pore domain. The mechanisms of gating in these channels have been intensely studied using pioneering methods such as measurement of charge displacement across a membrane, sequencing of genes coding for voltage-gated ion channels, and the development of all-atom molecular dynamics simulations using structural information from prokaryotic and eukaryotic channel proteins. One aspect of this work has been the description of the role of conserved negative countercharges in S1, S2, and S3 transmembrane segments to promote sequential salt-bridge formation with positively charged residues in S4 segments. These interactions facilitate S4 translocation through the lipid bilayer. In this review, we describe functional and computational work investigating the role of these countercharges in S4 translocation, voltage sensor domain hydration, and in diseases resulting from countercharge mutations.

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“…Together with a negatively charged residue on S3 helix, F3 and E4 on S2 form the so-called charge transfer center (CTC) at the bottom of VS (Tao et al, 2010). The S4 helix of functional VS is in the "down" conformation due to the negative voltage at resting membrane potential, while at depolarizing potential, S4 helix moves "up" in response to the changes of electrostatic field (Lee and MacKinnon, 2019;Wisedchaisri et al, 2019). In contrast to the canonical voltage-gated ion channels, some of the voltage sensors of NALCN are degenerated due to mutations of key residues in either charge-transfer center on S2 or gating charges on S4.…”

Section: Conformations Of Degenerated Voltage Sensors At Depolarizingmentioning

confidence: 99%

Structure of voltage-modulated sodium-selective NALCN-FAM155A channel complex

Chen

2020

Preprint

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Resting membrane potential determines the excitability of the cell and is essential for the cellular electrical activities. NALCN channel mediates sodium leak currents, which positively tune the resting membrane potential towards depolarization. NALCN channel is involved in many important neurological processes and is implicated in a spectrum of neurodevelopmental diseases. Despite its functional importance, the mechanisms of ion permeation and voltage-modulation for NALCN channel remain elusive. Here, we report the cryo-EM structure of rat NALCN and mouse FAM155A complex to 2.7 Å resolution. The structure reveals detailed interactions between NALCN and extracellular cysteine-rich domain of FAM155A. The non-canonical architecture of NALCN selectivity filter dictates its sodium selectivity and calcium block. The asymmetric arrangement of two functional voltage-sensors confers the modulation by membrane potential. Moreover, mutations found in human diseases were mapped to the domain-domain interfaces or the pore domain of NALCN, intuitively suggesting their pathological mechanisms.

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Resting-State Structure and Gating Mechanism of a Voltage-Gated Sodium Channel

Cited by 160 publications

References 83 publications

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

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

Roles for Countercharge in the Voltage Sensor Domain of Ion Channels

Structure of voltage-modulated sodium-selective NALCN-FAM155A channel complex

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