Localization of the Extracellular End of the Voltage Sensor S4 in a Potassium Channel

Elinder, Fredrik; Århem, Peter; Larsson, H. Peter

doi:10.1016/s0006-3495(01)76150-4

Cited by 45 publications

(77 citation statements)

References 34 publications

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“…In the resting state, we estimate that R362 is located >20 Å away from 418C. These distances are in agreement with the position of S4 that we suggested in our previous study (Elinder et al 2001). These results also show that more than half of the change in the electrostatic potential around 418C (19 out of 35 mV) is due to the movement of R362 toward 418C.…”

Section: Resultssupporting

confidence: 92%

“…To test the hypothesis that S4 is located close to S5 (Elinder and Århem 1999; Gandhi et al 2000; Loots and Isacoff 2000; Elinder et al 2001), we investigated the electrostatic impact that the movement of the charged residues of S4 has on residues in S5. We did this by introducing a cysteine at position 418 in the extracellular end of S5 and by measuring the rate of modification of 418C by charged cysteine-specific reagents at two different potentials at which S4 is either in a resting state (−80 mV) or in an activated state (0 mV).…”

Section: Resultsmentioning

confidence: 99%

“…For MTSET + , the two effects are opposing. Therefore, if S4 comes closer to 418C during activation (Elinder et al 2001), our expectation is that activation will increase the rate of modification for MTSES − , but the modification rate for MTSET + will essentially be unaltered (see materials and methods ). To test our assumptions about the different electrostatic effects more directly, we also conducted experiments with the neutral MMTS 0 , which only should be sensitive to changes in the protonation state of the cysteine.…”

Section: Resultsmentioning

confidence: 99%

“…Modification of 419C by MTSET + shifts the voltage dependence of the activation of the channels to more positive voltages, whereas MTSES − shifts it to more negative voltages (Elinder et al 2001). The modification rate of 419C channels by MTSET + in the resting state (−80 mV; τ = 0.6 mMs) was not significantly different from that in the activated state of S4 (0 mV; τ = 0.8 mMs; Table ).…”

Section: Resultsmentioning

confidence: 99%

“…S4 is suggested to undergo a large-scale movement during activation of the channels, either a 180° rotation (Papazian and Bezanilla 1997; Cha et al 1999; Glauner et al 1999) or a helical screw motion with both a 180° rotation and a translational motion of 13.5 Å (Catterall 1986; Guy and Seetharamulu 1986; Glauner et al 1999; Keynes and Elinder 1999; Gandhi et al 2000). In a recent study on the Shaker K channel, we suggested that S4, in the activated state, was located just outside S5 with the most external positive charge of S4 (R362) closest to the pore (Elinder et al 2001). If S4 is located close to S5 (Elinder and Århem 1999; Loots and Isacoff 2000), then a large-scale movement of the highly charged S4 is predicted to change the local electrostatic potential around S5 substantially.…”

Section: Introductionmentioning

confidence: 99%

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S4 Charges Move Close to Residues in the Pore Domain during Activation in a K Channel

Elinder

Männikkö

Larsson

2001

The Journal of General Physiology

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Voltage-gated ion channels respond to changes in the transmembrane voltage by opening or closing their ion conducting pore. The positively charged fourth transmembrane segment (S4) has been identified as the main voltage sensor, but the mechanisms of coupling between the voltage sensor and the gates are still unknown. Obtaining information about the location and the exact motion of S4 is an important step toward an understanding of these coupling mechanisms. In previous studies we have shown that the extracellular end of S4 is located close to segment 5 (S5). The purpose of the present study is to estimate the location of S4 charges in both resting and activated states. We measured the modification rates by differently charged methanethiosulfonate regents of two residues in the extracellular end of S5 in the Shaker K channel (418C and 419C). When S4 moves to its activated state, the modification rate by the negatively charged sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES−) increases significantly more than the modification rate by the positively charged [2-(trimethylammonium)ethyl] methanethiosulfonate, bromide (MTSET+). This indicates that the positive S4 charges are moving close to 418C and 419C in S5 during activation. Neutralization of the most external charge of S4 (R362), shows that R362 in its activated state electrostatically affects the environment at 418C by 19 mV. In contrast, R362 in its resting state has no effect on 418C. This suggests that, during activation of the channel, R362 moves from a position far away (>20 Å) to a position close (8 Å) to 418C. Despite its close approach to E418, a residue shown to be important in slow inactivation, R362 has no effect on slow inactivation or the recovery from slow inactivation. This refutes previous models for slow inactivation with an electrostatic S4-to-gate coupling. Instead, we propose a model with an allosteric mechanism for the S4-to-gate coupling.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

S4 Charges Move Close to Residues in the Pore Domain during Activation in a K Channel

Elinder

Männikkö

Larsson

2001

The Journal of General Physiology

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Effects of intracellular magnesium on Kv1.5 and Kv2.1 potassium channels

2004

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We characterized the effects of intracellular Mg(2+) (Mg(2+) (i)) on potassium currents mediated by the Kv1.5 and Kv2.1 channels expressed in Xenopus oocytes. Increase in Mg(2+) (i) caused a voltage-dependent block of the current amplitude, apparent acceleration of the current kinetics (explained by a corresponding shift in the steady-state activation) and leftward shifts in activation and inactivation dependencies for both channels. The voltage-dependent block was more potent for Kv2.1 [dissociation constant at 0 mV, K(d)(0), was approximately 70 mM and the electric distance of the Mg(2+) binding site, delta, was 0.2] than for the Kv1.5 channel [K(d)(0) approximately 40 mM and delta = 0.1]. Similar shifts in the voltage-dependent parameters for both channels were described by the Gouy-Chapman formalism with the negative charge density of 1 e(-)/100 A(2). Additionally, Mg(2+) (i) selectively reduced a non-inactivating current and increased the accumulation of inactivation of the Kv1.5, but not the Kv2.1 channel. A potential functional role of the differential effects of Mg(2+) (i) on the Kv channels is discussed.

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Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

Börjesson

Elinder

2008

Cell Biochem Biophys

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122

146

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Voltage-gated ion channels are crucial for both neuronal and cardiac excitability. Decades of research have begun to unravel the intriguing machinery behind voltage sensitivity. Although the details regarding the arrangement and movement in the voltage-sensing domain are still debated, consensus is slowly emerging. There are three competing conceptual models: the helical-screw, the transporter, and the paddle model. In this review we explore the structure of the activated voltage-sensing domain based on the recent X-ray structure of a chimera between Kv1.2 and Kv2.1. We also present a model for the closed state. From this we conclude that upon depolarization the voltage sensor S4 moves ~13 Å outwards and rotates ~180º, thus consistent with the helical-screw model. S4 also moves relative to S3b which is not consistent with the paddle model. One interesting feature of the voltage sensor is that it partially faces the lipid bilayer and therefore can interact both with the membrane itself and with physiological and pharmacological molecules reaching the channel from the membrane.This type of channel modulation is discussed together with other mechanisms for how voltage-sensitivity is modified. Small effects on voltage-sensitivity can have profound effects on excitability. Therefore, medical drugs designed to alter the voltage dependence offer an interesting way to regulate excitability.3

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Localization of the Extracellular End of the Voltage Sensor S4 in a Potassium Channel

Cited by 45 publications

References 34 publications

S4 Charges Move Close to Residues in the Pore Domain during Activation in a K Channel

S4 Charges Move Close to Residues in the Pore Domain during Activation in a K Channel

Effects of intracellular magnesium on Kv1.5 and Kv2.1 potassium channels

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

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