On the structural basis for ionic selectivity among Na+, K+, and Ca2+ in the voltage-gated sodium channel

Favre, Isabelle; Moczydlowski, Edward; Schild, Laurent

doi:10.1016/s0006-3495(96)79505-x

Cited by 242 publications

(338 citation statements)

References 65 publications

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“…Mutations of these key residues exhibit pronounced influence on the Na + selectivity and tetrodotoxin/saxitoxin binding affinity. Among the four key residues, Lys is indispensable for exclusion of Ca 2+ permeation and for discrimination between Na + and K + [23][24][25][26][27]. Mutating DEKA to EEEE transforms the Na v channel into a Ca 2+ -selective channel [28].…”

Section: Introductionmentioning

confidence: 99%

Analysis of the selectivity filter of the voltage-gated sodium channel NavRh

Zhang

Xia

et al. 2012

Cell Res

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NaChBac is a bacterial voltage-gated sodium (Na v ) channel that shows sequence similarity to voltage-gated calcium channels. To understand the ion-permeation mechanism of Na v channels, we combined molecular dynamics simulation, structural biology and electrophysiological approaches to investigate the recently determined structure of Na v Rh, a marine bacterial NaChBac ortholog. Two Na + binding sites are identified in the selectivity filter (SF) in our simulations: The extracellular Na + ion first approaches site 1 constituted by the side groups of Ser181 and Glu183, and then spontaneously arrives at the energetically more favorable site 2 formed by the carbonyl oxygens of Leu179 and Thr178. In contrast, Ca 2+ ions are prone to being trapped by Glu183 at site 1, which then blocks the entrance of both Na + and Ca 2+ to the vestibule of the SF. In addition, Na + permeates through the selective filter in an asymmetrical manner, a feature that resembles that of the mammalian Na v orthologs. The study reported here provides insights into the mechanism of ion selectivity on Na + over Ca 2+ in mammalian Na v channels.

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Section: Introductionmentioning

confidence: 99%

Analysis of the selectivity filter of the voltage-gated sodium channel NavRh

Zhang

Xia

et al. 2012

Cell Res

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“…Only two residues in the four P-loop SS2 segments are different, Tyr-401 (numbering of 1, the adult rat skeletal muscle Na ϩ channel) in place of Phe (brain) or Cys (heart), and Asn-404 (skeletal muscle and brain) in place of Arg (heart). If QX access is through the pore, Tyr͞Phe͞Cys would be more likely to influence QX access than Asn͞Asn͞Arg because Tyr͞Phe͞Cys is one residue C-terminal to the selectivity filter (23,24). The residue at this position is thought to be located within the water-filled vestibule, rather than buried in the protein because it interacts strongly with the charged guanidinium toxins (11)(12)(13)(14).…”

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confidence: 99%

A critical residue for isoform difference in tetrodotoxin affinity is a molecular determinant of the external access path for local anesthetics in the cardiac sodium channel

Sunami

Glaaser

Fozzard

2000

Proc. Natl. Acad. Sci. U.S.A.

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Membrane-impermeant quaternary derivatives of lidocaine (QX222 and QX314) block cardiac Na ؉ channels when applied from either side of the membrane, but they block neuronal and skeletal muscle channels poorly from the outside. To find the molecular determinants of the cardiac external QX access path, mutations of adult rat skeletal muscle ( 1) and rat heart (rH1) Na ؉ channels were studied by two-electrode voltage clamp in Xenopus oocytes. Mutating the 1 domain I P-loop Y401, which is the critical residue for isoform differences in tetrodotoxin block, to the heart sequence (Y401C) allowed outside QX222 block, but its mutation to brain type (Y401F) showed little block. 1-Y401C accelerated recovery from block by internal QX222. Block by external QX222 in 1-Y401C was diminished by chemical modification with methanethiosulfonate ethylammonium (MTSEA) to the outer vestibule or by a double mutant ( 1-Y401C͞F1579A), which altered the putative local anesthetic binding site. The reverse mutation in heart rH1-C374Y reduced outside QX314 block and slowed dissociation of internal QX222. Mutation of 1-C1572 in IVS6 to Thr, the cardiac isoform residue (C1572T), allowed external QX222 block, and accelerated recovery from internal QX222 block, as reported. Blocking efficacy of outside QX222 in 1-Y401C was more than that in 1-C1572T, and the double mutant ( 1-Y401C͞C1572T) accelerated internal QX recovery more than 1-Y401C or 1-C1572T alone. We conclude that the isoform-specific residue (Tyr͞Phe͞Cys) in the P-loop of domain I plays an important role in drug access as well as in tetrodotoxin binding. Isoform-specific residues in the IP-loop and IVS6 determine outside drug access to an internal binding site.V oltage-gated Na ϩ channels are membrane proteins responsible for generation of action potentials in nerve, skeletal muscle, and heart. The Na ϩ channel ␣-subunit consists of four homologous domains (I-IV), each containing six transmembrane segments (S1-S6) (1, 2). P-loops connecting S5 and S6 in each domain form the Na ϩ channel outer vestibule (3-7). Na ϩ channel isoforms from various tissues are highly homologous (2, 8). However, cardiac channels are relatively insensitive to tetrodotoxin (TTX) compared with brain and skeletal muscle channels (9, 10). This isoform difference is explained by an isoformspecific residue (Tyr͞Phe͞Cys) in the P-loop of domain I (IP-loop) (11-14) (Fig. 1). An aromatic residue at this position renders the channel TTX sensitive.The Na ϩ channel is also the site of action of local anesthetic antiarrhythmic drugs. Two conserved aromatic residues (Phe and Tyr) in IVS6 are involved in the local anesthetic binding site (15)(16)(17), and isoform differences in local anesthetic affinity are much less than in toxin affinity (18). In contrast, access of local anesthetic drugs differs markedly between Na ϩ channel isoforms. Quaternary membrane-impermeant derivatives of lidocaine such as QX314 and QX222 do not block nerve channels when applied to the outside (19,20), but outside QX314 blocks the cardiac chann...

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“…13 The key chemical interactions due to aspartate and glutamate must arise from the carboxylate unit present in their side chains. 12 Also, this assumption is supported by the fact that mutation of a glutamate by an aspartate in the calcium channel reduces the binding site affinity, but not the selectivity. 13 Along the same lines, the alkyl ammonium group in the lysine side chain is expected to be important in determining its role in the selectivity filter.…”

Section: Choice Of the Model And Computational Methodologymentioning

confidence: 99%

“…The other amino acid residues are known to play only a minor role in selectivity. 12 Hence, DEK are the essential determinants of selectivity for a sodium channel. On the other hand, four glutamates have been characterized as constituting the selectivity filter in wild-type calcium channels.…”

Section: Choice Of the Model And Computational Methodologymentioning

confidence: 99%

“…12,13 Furthermore, experiments to understand molecular basis of proton block in calcium channels strongly suggest that glutamate in the fourth homology domain has a limited role in stabilization of the bound cation. 22 Therefore, it is reasonable to assume that it may not participate in direct binding with the ion passing through.…”

Section: Choice Of the Model And Computational Methodologymentioning

confidence: 99%

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Modeling of ion permeation in calcium and sodium channel selectivity filters

et al. 2000

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Structure-function studies have shown that it is possible to convert a sodium channel to a calcium-selective channel by a single amino acid substitution in the selectivity filter locus. Ion permeation through the "model selectivity filter" was modeled with a reduced set of functional groups representative of the constituent amino acid side chains. Force-field minimizations were conducted to obtain the energy profile of the cations as they get desolvated and bind to the "model selectivity filter." The calculations suggest that the ion selectivity in the calcium channel is due to preferential binding, whereas in the sodium channel it is due to exclusion. Energetics of displacement of a bound cation from the calcium "model selectivity filter" by another cation suggest that "multi-ion mechanism" reduces the activation barrier for ion permeation. Thus, the simple model captures qualitatively most of the conduction characteristics of sodium and calcium channels. However, the computed barriers for permeation are fairly large, suggesting that ion interaction with additional residues along the transport path may be essential to effect desolvation.

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On the structural basis for ionic selectivity among Na+, K+, and Ca2+ in the voltage-gated sodium channel

Cited by 242 publications

References 65 publications

Analysis of the selectivity filter of the voltage-gated sodium channel NavRh

Analysis of the selectivity filter of the voltage-gated sodium channel NavRh

A critical residue for isoform difference in tetrodotoxin affinity is a molecular determinant of the external access path for local anesthetics in the cardiac sodium channel

Modeling of ion permeation in calcium and sodium channel selectivity filters

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