Fine-tuning of Voltage Sensitivity of the Kv1.2 Potassium Channel by Interhelix Loop Dynamics

Sand, Rheanna; Sharmin, Nazlee; Morgan, Carla; Gallin, Warren J.

doi:10.1074/jbc.m112.437483

Cited by 13 publications

(17 citation statements)

References 46 publications

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“…The results of this study show that the effects of mutations that vary loop length and sequence on P. penicillatus jShak1 are substantially different from the effects of comparable mutations on mouse Kv1.2 channels (Sand et al, 2013). The length of these loops affects the voltage sensitivity of the channel, at least in part by constraining the relative movement of the S3 and S4 helices.…”

Section: Introductionmentioning

confidence: 76%

“…The results of a mouse Kv1.2 study (Sand et al, 2013) demonstrate an energetic constraint in the movement of the S4 helix by extremely short S3-S4 linkers. Depending on composition, the C-terminal end of the mouse S3-S4 linker also differentially affected the equilibrium between open and closed states of the channel by interacting with the negatively charged turret of the pore domain (Sand et al, 2013), as this part of the P loop is positioned in close proximity to the negatively charged residues of VSD during channel closure (Jensen et al, 2012). In D. melanogaster, mutations that shorten the S3-S4 linker tend to shift the V 50 to more positive values and decrease the rate of channel activation (Priest et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…In the mouse Kv1.2 channel, the C-terminal region of the S3-S4 linker is proposed to be pulled downward on channel deactivation and the VSD rotates towards the PD, bringing the C-terminal end of the S3-S4 loop closer to the negatively charged residues of the VSD and the PD turret in the closed state (Jensen et al, 2012); mutations of this C-terminal region significantly affect the V 50 of mouse Kv1.2 (Sand et al, 2013). We mutated the C-terminal residue of the S3-S4 loop of jShak1 in both natural and synthetic loops to evaluate the effect of the C-terminal residue of the S3-S4 linker on the V 50 values of jShak1.…”

Section: Effects Of Mutation Of the C-terminal Residue Of The S3-s4 Loopmentioning

confidence: 99%

“…A lobe of ovary was surgically extracted from female X. laevis of 2-4 years of age and single oocytes were prepared and injected with synthesized mRNA as previously described (Sand et al, 2013). The protocols used for preparing oocytes from X. laevis were evaluated and approved by the Animal Care and Use Committee (Biosciences) of the University of Alberta ( protocol AUP00000011).…”

Section: Oocyte Preparationmentioning

confidence: 99%

“…Previous studies with mouse Kv1.2 (Sand et al, 2013) and D. melanogaster Shaker (Gonzalez et al, 2001;Priest et al, 2013) indicated a role for the S3-S4 loop length and composition in setting the V 50 of activation of the channel. The results of a mouse Kv1.2 study (Sand et al, 2013) demonstrate an energetic constraint in the movement of the S4 helix by extremely short S3-S4 linkers.…”

Section: Introductionmentioning

confidence: 99%

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Intramolecular interactions that control voltage sensitivity in the jShak1 potassium channel from Polyorchis penicillatus

Sharmin

Gallin

2016

Journal of Experimental Biology

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Voltage-gated potassium ion (Kv) channel proteins respond to changes in membrane potential by changing the probability of K + flux through an ion-selective pore. Kv channels from different paralogous and orthologous families have widely varying V 50 values. The voltage-sensing transmembrane helices (S4) of different channels contain four to seven basic residues that are responsible for transducing changes in transmembrane potential into the energy required to shift the equilibrium between the open-and closed-channel conformations. These residues also form electrostatic interaction networks with acidic residues in the S2 and S3 helices that stabilize the open and the closed states to different extents. The length and composition of the extracellular loop connecting the S3 and S4 helices (S3-S4 loop) also shape the voltage response. We describe mutagenesis experiments on the jellyfish (Polyorchis penicillatus) Kv1 family jShak1 channel to evaluate how variants of the S3-S4 loop affect the voltage sensitivity of this channel. In combination with changes in the length and composition of the S3-S4 linker, we mutated a residue on the S2 helix (N227) that in most Kv1 family channels is glutamate (E226 in mouse Kv1.2, E283 in D. melanogaster Shaker). Some individual loop replacement mutants cause major changes in voltage sensitivity, depending on a combination of length and composition. Pairwise combinations of the loop mutations and the S2 mutations interact to yield quantitatively distinct, non-additive changes in voltage sensitivity. We conclude that the S3-S4 loop interacts energetically with the residue at position N227 during the transitions between open and closed states of the channel.

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Section: Introductionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Section: Effects Of Mutation Of the C-terminal Residue Of The S3-s4 Loopmentioning

confidence: 99%

Section: Oocyte Preparationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Intramolecular interactions that control voltage sensitivity in the jShak1 potassium channel from Polyorchis penicillatus

Sharmin

Gallin

2016

Journal of Experimental Biology

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Functional characterization of Kv11.1 (hERG) potassium channels split in the voltage-sensing domain

Peña

Domı́nguez

Barros

2018

Pflugers Arch - Eur J Physiol

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Voltage-dependent KCNH family potassium channel functionality can be reconstructed using non-covalently linked voltage-sensing domain (VSD) and pore modules (split channels). However, the necessity of a covalent continuity for channel function has not been evaluated at other points within the two functionally independent channel modules. We find here that by cutting Kv11.1 (hERG, KCNH2) channels at the different loops linking the transmembrane spans of the channel core, not only channels split at the S4–S5 linker level, but also those split at the intracellular S2–S3 and the extracellular S3–S4 loops, yield fully functional channel proteins. Our data indicate that albeit less markedly, channels split after residue 482 in the S2–S3 linker resemble the uncoupled gating phenotype of those split at the C-terminal end of the VSD S4 transmembrane segment. Channels split after residues 514 and 518 in the S3–S4 linker show gating characteristics similar to those of the continuous wild-type channel. However, breaking the covalent link at this level strongly accelerates the voltage-dependent accessibility of a membrane impermeable methanethiosulfonate reagent to an engineered cysteine at the N-terminal region of the S4 transmembrane helix. Thus, besides that of the S4–S5 linker, structural integrity of the intracellular S2–S3 linker seems to constitute an important factor for proper transduction of VSD rearrangements to opening and closing the cytoplasmic gate. Furthermore, our data suggest that the short and probably rigid characteristics of the extracellular S3–S4 linker are not an essential component of the Kv11.1 voltage sensing machinery.Electronic supplementary materialThe online version of this article (10.1007/s00424-018-2135-y) contains supplementary material, which is available to authorized users.

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Impact of geometry changes in the channel pore by the gating movements on the channel’s conductance

Wawrzkiewicz-Jałowiecka¹,

Borys²,

Grzywna³

2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Kv 1.2 are voltage-dependent potassium channels of great biological importance. Despite the existence of many reports considering structure - function relations of the Kv 1.2 channel's quantitative domains, some details of the voltage gating remain ambiguous, or even unknown. One of the examples is the range of the S4-S6 domains motions involved in channel activation and gating. Another important question is to what extent the channel geometry influences the observable channel conductance at different voltages, and what mechanism stands behind. Does the narrowing of the pore reduce the conductance by ohmic resistance growth? The answer is surprisingly negative. But it can be explained in an alternative way by considering the fluctuations. To address these problems, we formulate geometric models that mimic the generic features of voltage sensor movement and trigger the movement of the other domains involved in gating. We carry out a complete simulation of S4-S6 domains translations and tilts. The obtained pore profiles allow to estimate the (ohmic) conductance dependency on the voltage. From a family of analysed models, we choose the one most concurring with the experimental data. The results allow to suggest the most probable scenario of S4-S6 domains movement during channel activation by membrane depolarization.

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Fine-tuning of Voltage Sensitivity of the Kv1.2 Potassium Channel by Interhelix Loop Dynamics

Cited by 13 publications

References 46 publications

Intramolecular interactions that control voltage sensitivity in the jShak1 potassium channel from Polyorchis penicillatus

Intramolecular interactions that control voltage sensitivity in the jShak1 potassium channel from Polyorchis penicillatus

Functional characterization of Kv11.1 (hERG) potassium channels split in the voltage-sensing domain

Impact of geometry changes in the channel pore by the gating movements on the channel’s conductance

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