Divalent Cation Effects on the Shaker K Channel Suggest a Pentapeptide Sequence as Determinant of Functional Surface Charge Density

Elinder, Fredrik; Liu, Y; Århem, Peter

doi:10.1007/s002329900432

Cited by 19 publications

(12 citation statements)

References 20 publications

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“…We have previously identified charged residues that contribute to j out and to V 1/2 (13,15,48). However, we have not been able to completely transfer the effective surface charges from a metal-ion sensitive channel to a relatively metal ion-insensitive channel.…”

Section: Strontium Effects On Seven Wild-type Kv Channelsmentioning

confidence: 84%

Extracellular Linkers Completely Transplant the Voltage Dependence from Kv1.2 Ion Channels to Kv2.1

Elinder

Madeja

Zeberg

et al. 2016

Biophysical Journal

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The transmembrane voltage needed to open different voltage-gated K (Kv) channels differs by up to 50 mV from each other. In this study we test the hypothesis that the channels' voltage dependences to a large extent are set by charged amino-acid residues of the extracellular linkers of the Kv channels, which electrostatically affect the charged amino-acid residues of the voltage sensor S4. Extracellular cations shift the conductance-versus-voltage curve, G(V), by interfering with these extracellular charges. We have explored these issues by analyzing the effects of the divalent strontium ion (Sr 2þ ) on the voltage dependence of the G(V) curves of wild-type and chimeric Kv channels expressed in Xenopus oocytes, using the voltage-clamp technique. Out of seven Kv channels, Kv1.2 was found to be most sensitive to Sr 2þ (50 mM shifted G(V) by þ21.7 mV), and Kv2.1 to be the least sensitive (þ7.8 mV). Experiments on 25 chimeras, constructed from Kv1.2 and Kv2.1, showed that the large Sr 2þ -induced G(V) shift of Kv1.2 can be transferred to Kv2.1 by exchanging the extracellular linker between S3 and S4 (L3/4) in combination with either the extracellular linker between S5 and the pore (L5/P) or that between the pore and S6 (LP/6). The effects of the linker substitutions were nonadditive, suggesting specific structural interactions. The free energy of these interactions was~20 kJ/mol, suggesting involvement of hydrophobic interactions and/or hydrogen bonds. Using principles from double-layer theory we derived an approximate linear equation (relating the voltage shifts to altered ionic strength), which proved to well match experimental data, suggesting that Sr 2þ acts on these channels mainly by screening surface charges. Taken together, these results highlight the extracellular surface potential at the voltage sensor as an important determinant of the channels' voltage dependence, making the extracellular linkers essential targets for evolutionary selection.

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Section: Strontium Effects On Seven Wild-type Kv Channelsmentioning

confidence: 84%

Extracellular Linkers Completely Transplant the Voltage Dependence from Kv1.2 Ion Channels to Kv2.1

Elinder

Madeja

Zeberg

et al. 2016

Biophysical Journal

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“…Negative charges on residues of the extracellular loop connecting the S5 and pore-forming P-loop segments of Kv channels determine the voltage for activating the channel (Elinder et al 1998; Elinder and Århem 1999). One residue is conserved in that region — E418 for ShakerB — while others are variable.…”

Section: Resultsmentioning

confidence: 99%

The sliding-helix voltage sensor: mesoscale views of a robust structure–function relationship

Peyser

Nonner

2012

Eur Biophys J

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The voltage sensor (VS) domain of voltage-gated ion channels underlies electrical excitability of living cells. We simulate a mesoscale model of the VS domain to determine the functional consequences of some of its physical elements. Our mesoscale model is based on VS charges, linear dielectrics and whole-body motion, applied to an S4 ‘sliding helix’. The electrostatics under voltage-clamped boundary conditions are solved consistently using a boundary element method. Based on electrostatic configurational energy, statistical-mechanical expectations of the experimentally observable relation between displaced charge and membrane voltage are predicted. Consequences of the model are investigated for variations of: S4 configuration (α- and 310-helical), countercharge alignment with S4 charges, protein polarizability, geometry of the gating canal, screening of S4 charges by the baths, and fixed charges located at the bath interfaces. The sliding helix VS domain has an inherent electrostatic stability in the explored parameter space: countercharges present in the region of weak dielectric always retain an equivalent S4 charge in that region but allow sliding movements displacing 3 to 4 e0. That movement is sensitive to small energy variations (< 2kT) along the path dependent on a number of electrostatic parameters tested in our simulations. These simulations show how the slope of the relation between displaced charge and voltage could be tuned in a channel.

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“…However, the magnitude of an effect of altered bilayer charge on potential-dependent channel parameters remains unknown. Given that the Debye length for electrostatic interactions under physiological conditions (estimated at 9 Å) is shorter than the predicted dimensions of the channel protein (42,43), the gating charges of the channel appear to be partially insulated from surrounding bilayer charge. Therefore, the channel may not sense the full value of the surface potential in the charged lipid.…”

Section: Kv15 Raft Association Does Not Involve Cooh-terminalmentioning

confidence: 94%

Isoform-specific Localization of Voltage-gated K+Channels to Distinct Lipid Raft Populations

Martens

Sakamoto

Sullivan

et al. 2001

Journal of Biological Chemistry

211

203

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The precise subcellular localization of ion channels is often necessary to ensure rapid and efficient integration of both intracellular and extracellular signaling events. Recently, we have identified lipid raft association as a novel mechanism for the subcellular sorting of specific voltage-gated K ؉ channels to regions of the membrane rich in signaling complexes. Here, we demonstrate isoform-specific targeting of voltage-gated K ؉ (Kv) channels to distinct lipid raft populations with the finding that Kv1.5 specifically targets to caveolae. Multiple lines of evidence indicate that Kv1.5 and Kv2.1 exist in distinct raft domains: 1) channel/raft association shows differential sensitivity to increasing concentrations of Triton X-100; 2) unlike Kv2.1, Kv1.5 colocalizes with caveolin on the cell surface and redistributes with caveolin following microtubule disruption; and 3) immunoisolation of caveolae copurifies Kv1.5 channel. Both depletion of cellular cholesterol and inhibition of sphingolipid synthesis alter Kv1.5 channel function by inducing a hyperpolarizing shift in the voltage dependence of activation and inactivation. The differential targeting of Kv channel subtypes to caveolar and noncaveolar rafts within a single membrane represents a unique mechanism of compartmentalization, which may permit isoform-specific modulation of K ؉ channel function.

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Divalent Cation Effects on the Shaker K Channel Suggest a Pentapeptide Sequence as Determinant of Functional Surface Charge Density

Cited by 19 publications

References 20 publications

Extracellular Linkers Completely Transplant the Voltage Dependence from Kv1.2 Ion Channels to Kv2.1

Extracellular Linkers Completely Transplant the Voltage Dependence from Kv1.2 Ion Channels to Kv2.1

The sliding-helix voltage sensor: mesoscale views of a robust structure–function relationship

Isoform-specific Localization of Voltage-gated K+Channels to Distinct Lipid Raft Populations

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