Conduction in a Biological Sodium Selective Channel

Stock, Letícia; Delemotte, Lucie; Carnevale, Vincenzo; Treptow, Werner; Klein, Michael L.

doi:10.1021/jp401403b

Cited by 58 publications

(105 citation statements)

References 29 publications

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“…Water molecules are likely to play a crucial role in screening these unbalanced charges in the basic region. A similar scenario was observed in the sodium channel NavAb (25). Due to the excess positive charge in the basic region, electrostatic repulsion between the channel and the cation is likely to squeeze cations out of this region.…”

Section: Resultssupporting

confidence: 57%

Pore waters regulate ion permeation in a calcium release-activated calcium channel

Dong

Fiorin

Carnevale

et al. 2013

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

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128

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The recent crystal structure of Orai, the pore unit of a calcium release-activated calcium (CRAC) channel, is used as the starting point for molecular dynamics and free-energy calculations designed to probe this channel's conduction properties. In free molecular dynamics simulations, cations localize preferentially at the extracellular channel entrance near the ring of Glu residues identified in the crystal structure, whereas anions localize in the basic intracellular half of the pore. To begin to understand ion permeation, the potential of mean force (PMF) was calculated for displacing a single Na + ion along the pore of the CRAC channel. The computed PMF indicates that the central hydrophobic region provides the major hindrance for ion diffusion along the permeation pathway, thereby illustrating the nonconducting nature of the crystal structure conformation. Strikingly, further PMF calculations demonstrate that the mutation V174A decreases the free energy barrier for conduction, rendering the channel effectively open. This seemingly dramatic effect of mutating a nonpolar residue for a smaller nonpolar residue in the pore hydrophobic region suggests an important role for the latter in conduction. Indeed, our computations show that even without significant channel-gating motions, a subtle change in the number of pore waters is sufficient to reshape the local electrostatic field and modulate the energetics of conduction, a result that rationalizes recent experimental findings. The present work suggests the activation mechanism for the wild-type CRAC channel is likely regulated by the number of pore waters and hence pore hydration governs the conductance.store-operated calcium entry | computer simulation C alcium release-activated calcium (CRAC) channels in the plasma membrane are integral membrane proteins that play a central role in cellular signaling by generating the sustained influx of calcium (1-3). Immune response in cells consists typically of a fall in Ca 2+ content within the endoplasmic reticulum (ER), followed by the opening of the store-operated CRAC channels that leads to the sustained increase in intracellular Ca 2+ concentrations (4). Despite about two decades of research, the molecular components underlying this process of store-operated calcium entry (SOCE) have been unknown until recently, when the stromal interaction molecule (STIM) was determined to be the ER Ca 2+ sensor (5, 6) that activates the channel in response to the depletion of intracellular calcium store content. Later, the Orai protein was identified as the pore subunit of the channel (7-9). CRAC regulator 2A was then discovered to reinforce the binding of the two aforementioned key components at elevated Ca 2+ levels to promote the SOCE, and to inhibit the influx at low Ca 2+ levels by dissociating from the complex (10). The newly published crystal structure of the CRAC channel pore subunit, Orai, from Drosophila melanogaster at 3.35 Å resolution, provides groundbreaking insights into a molecular architecture that is distinct from ...

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Section: Resultssupporting

confidence: 57%

Pore waters regulate ion permeation in a calcium release-activated calcium channel

Dong

Fiorin

Carnevale

et al. 2013

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

Self Cite

128

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“…That study reports different binding modes and a lower average Na + occupancy of the SF than the present analysis. These discrepancies may be due, at least in part, to the presence of a large, negative internal voltage (23,25), which could shift the conformational equilibrium of E177 toward the outfacing rotamer and perturb the catalytic mechanism reported in the present study.…”

Section: Methodsmentioning

confidence: 54%

“…Several simulation studies have recently examined the energetics and the dynamics of Na + , Ca 2+ , and K + in the SF of Na V Ab (18)(19)(20)(21)(22)(23)(24)(25). Consistent with the above results, some of these studies described coordination of Na + by the carboxyl group of E177 (18,20,21,24) and a two-ion knock-on mechanism (19,20,23,24) involving low free energy barriers (19,22,23). In addition, χ 2 conformational isomerization of E177 was reported in a simulation of Ca 2+ permeation (24).…”

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confidence: 99%

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Catalysis of Na ⁺ permeation in the bacterial sodium channel Na _V Ab

Chakrabarti

Ing

Payandeh

et al. 2013

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

116

147

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Determination of a high-resolution 3D structure of voltage-gated sodium channel Na V Ab opens the way to elucidating the mechanism of ion conductance and selectivity. To examine permeation of Na + through the selectivity filter of the channel, we performed large-scale molecular dynamics simulations of Na V Ab in an explicit, hydrated lipid bilayer at 0 mV in 150 mM NaCl, for a total simulation time of 21.6 μs. Although the cytoplasmic end of the pore is closed, reversible influx and efflux of Na + through the selectivity filter occurred spontaneously during simulations, leading to equilibrium movement of Na + between the extracellular medium and the central cavity of the channel. Analysis of Na + dynamics reveals a knock-on mechanism of ion permeation characterized by alternating occupancy of the channel by 2 and 3 Na + ions, with a computed rate of translocation of (6 ± 1) × 10 6 ions·s −1 that is consistent with expectations from electrophysiological studies. The binding of Na + is intimately coupled to conformational isomerization of the four E177 side chains lining the extracellular end of the selectivity filter. The reciprocal coordination of variable numbers of Na + ions and carboxylate groups leads to their condensation into ionic clusters of variable charge and spatial arrangement. Structural fluctuations of these ionic clusters result in a myriad of ion binding modes and foster a highly degenerate, liquidlike energy landscape propitious to Na + diffusion. By stabilizing multiple ionic occupancy states while helping Na + ions diffuse within the selectivity filter, the conformational flexibility of E177 side chains underpins the knock-on mechanism of Na + permeation.T he rapid passage of cations in and out of excitable cells through selective pathways underlies the generation and regulation of electrical signals in all living organisms (1-4). The metazoan cell membrane is exposed to a high-Na + , low-K + concentration on the extracellular (EC) side, and to a low-Na + , high-K + concentration on the intracellular (IC) side. Selective voltage-gated Na + and K + channels control the response of the cell to changes in the membrane potential. In particular, voltagegated Na + channels (Na V ) are responsible for the initiation and propagation of action potentials in cardiac and skeletal myocytes, neurons, and endocrine cells (1-4). Mutations in Na V channel genes are responsible for a wide range of debilitating channelopathies, including congenital epilepsy, paramyotonia, erythromelalgia, familial hemiplegic migraine, paroxysmal extreme pain disorder, and periodic paralyses (5, 6), underlining the importance of deciphering the relationship between the structure and function of Na V channels. Here, we use molecular simulations to study the binding and permeation of Na + in bacterial sodium channel Na V Ab.Although several atomic structures of K + -selective channels have been solved over the past decade (7-12), the atomic structure of an Na + -selective channel from the bacterium Arcobacter butzleri, Na V Ab, wa...

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“…The resolution of the first such structure (3.5 Å), however, was too low to determine the details of the sites of the ions in the SF, whilst the latter structures contained channel blocker ligands which interfered with ion binding. The sodium ion binding site locations and mechanisms for ion selectivity have also been predicted by a number of molecular dynamics (MD) studies, although they differ considerably in their details (Amaral et al , 2012; Chakrabarti et al , 2013; Stock et al , 2013; Ulmschneider et al , 2013; Xia et al , 2013; Zhang et al , 2013; Boiteux et al , 2014; Furini et al , 2014). …”

Section: Introductionmentioning

confidence: 99%

Molecular basis of ion permeability in a voltage‐gated sodium channel

et al. 2016

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Voltage‐gated sodium channels are essential for electrical signalling across cell membranes. They exhibit strong selectivities for sodium ions over other cations, enabling the finely tuned cascade of events associated with action potentials. This paper describes the ion permeability characteristics and the crystal structure of a prokaryotic sodium channel, showing for the first time the detailed locations of sodium ions in the selectivity filter of a sodium channel. Electrostatic calculations based on the structure are consistent with the relative cation permeability ratios (Na+ ≈ Li+ ≫ K+, Ca2+, Mg2+) measured for these channels. In an E178D selectivity filter mutant constructed to have altered ion selectivities, the sodium ion binding site nearest the extracellular side is missing. Unlike potassium ions in potassium channels, the sodium ions in these channels appear to be hydrated and are associated with side chains of the selectivity filter residues, rather than polypeptide backbones.

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Conduction in a Biological Sodium Selective Channel

Cited by 58 publications

References 29 publications

Pore waters regulate ion permeation in a calcium release-activated calcium channel

Pore waters regulate ion permeation in a calcium release-activated calcium channel

Catalysis of Na ⁺ permeation in the bacterial sodium channel Na _V Ab

Molecular basis of ion permeability in a voltage‐gated sodium channel

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Conduction in a Biological Sodium Selective Channel

Cited by 58 publications

References 29 publications

Pore waters regulate ion permeation in a calcium release-activated calcium channel

Pore waters regulate ion permeation in a calcium release-activated calcium channel

Catalysis of Na + permeation in the bacterial sodium channel Na V Ab

Molecular basis of ion permeability in a voltage‐gated sodium channel

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Catalysis of Na ⁺ permeation in the bacterial sodium channel Na _V Ab