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

Börjesson, Sara I.; Elinder, Fredrik

doi:10.1007/s12013-008-9032-5

Cited by 119 publications

(134 citation statements)

References 259 publications

(356 reference statements)

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“…For such a comparison we here use the results from a highresolution structure of a Kv1.2/2.1 chimera, crystallized in the presence of phospholipids (39). This chimera is essentially a Kv1.2 channel with the extracellular end of S3, the L3/4 linker, and the extracellular end of S4 from Kv2.1, and this structure most likely captures the detailed structural features of a native Kv channel (16,49,55). Kv2.1 and Kv1.2 differs in a few positions in the extracellular linkers L3/4, L5/P, and LP/6 with respect to charged amino acid residues (Fig.…”

Section: Molecular Interpretation Of Linker Substitutionsmentioning

confidence: 99%

“…V 1/2 has been shown to depend on the existence of certain charged residues on the external surface of the channel protein (11)(12)(13), suggesting these charges contribute to an electric potential at the external surface (14)(15)(16). Metal ions were early recognized to alter the excitability of neurons by shifting the G(V) curve of ion channels along the voltage axis (17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

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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: Molecular Interpretation Of Linker Substitutionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…It has even been proposed that the VSD undergoes a conformational alteration following the opening, when the channel relaxes to an inactivated, that is closed, state (9). In addition to conferring voltage dependence to ion channels, VSDs also regulate enzymes (10), act as voltage-gated proton channels (11,12), are susceptible to disease-causing mutations (13,14), and serve as targets for drugs and toxins (1,(15)(16)(17)(18). Therefore, it is of crucial interest to understand the details underlying voltage sensing by VSDs.…”

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confidence: 99%

“…To sense changes in membrane voltage, each ion channel is equipped with four voltage-sensor domains (VSDs) connected to a central ion-conducting pore domain. The fourth transmembrane segment (S4) of each VSD carries several positively charged amino-acid residues responsible for VSD gating (1). At least three elementary charges per VSD must traverse outwards through the membrane electric field to open a channel that corresponds to a considerable displacement of the S4 helix ( Fig.…”

mentioning

confidence: 99%

Tracking a complete voltage-sensor cycle with metal-ion bridges

Henrion

Renhorn

Börjesson

et al. 2012

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

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Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 Å along its axis to open the channel with a 3 10 helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states. V oltage-gated ion channels are critical for biological signaling, and they are able to regulate ion flux on a millisecond time scale. To sense changes in membrane voltage, each ion channel is equipped with four voltage-sensor domains (VSDs) connected to a central ion-conducting pore domain. The fourth transmembrane segment (S4) of each VSD carries several positively charged amino-acid residues responsible for VSD gating (1). At least three elementary charges per VSD must traverse outwards through the membrane electric field to open a channel that corresponds to a considerable displacement of the S4 helix ( Fig. 1A) (2-4). The positive charges in S4 make salt bridges with negative countercharges on their move through the VSD (4-8). It has even been proposed that the VSD undergoes a conformational alteration following the opening, when the channel relaxes to an inactivated, that is closed, state (9). In addition to conferring voltage dependence to ion channels, VSDs also regulate enzymes (10), act as voltage-gated proton channels (11,12), are susceptible to disease-causing mutations (13,14), and serve as targets for drugs and toxins (1,(15)(16)(17)(18). Therefore, it is of crucial interest to understand the details underlying voltage sensing by VSDs.Few, if any, segments of membrane proteins have received more attention than the S4 helix of voltage sensors. In addition to their paramount biological importance, they can help us understand fundamental biophysical problems such as why some membrane protein segments can be hydrophilic (19), how charges effectively move through a membrane, or how a potential triggers structural changes on a microsecond time scale. These questions are inherently linked to transient conformations and contacts that can be difficult to capture in a single structure. Although active...

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“…Together with other polyunsaturated fatty acids, DHA can modulate their fluidity and the activity of proteins contained by these membranes (enzymes, receptors, transporters, voltage-gated ion channels, etc.). These polyunsaturated fatty acids including DHA can directly affect the activity of membrane proteins like voltage-gated ion channels (Börjesson and Elinder, 2008).…”

Section: Bioavailability Of Estradiol Through Dhamentioning

confidence: 99%

Evolution of the Human Brain: the key roles of DHA (omega-3 fatty acid) and Δ6-desaturase gene

Majou

2018

OCL

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-The process of hominization involves an increase in brain size. The development of hominids' cognitive capital up to the emergence of Homo sapiens was due to interactive, iterative, and integrative coevolution, allowing positive selection. Although this depends on many factors, in this position paper we show three categories that stand out: gene mutations, food resources, and cognitive and behavioral stimulation. Australopithecus benefited both from the inactivation of the GULO and uricase genes and from bipedalism causing the cognitive capital of the Homo genus to develop advantageously. This evolution depended on two factors. Firstly, a triggering factor: gradual climate change. Homo started to regularly consume meat in addition to plants and insects. Secondly, a stimulating factor: mutations in the FADS2 gene, which encodes D6-desaturase; a key enzyme for the synthesis of DHA and sapienic acid. The polymorphism of this gene appears to have been essential in allowing the Homo genus to adapt to its food, and for its evolution. It provides an undeniable advantage in terms of the productivity of fat synthesis (DHA), and may partly explain positive selection. With the advent of cooking and new mutations producing even more FADS2, the brain reached its maximum size in Homo neanderthalensis, in a food ecosystem that provided favorable quantities of a-Linolenic acid and DHA. However, the Würm glaciation upset this equilibrium, revealing its fragility as regards to the brain and fertility. Homo sapiens, benefiting from new variants of the FADS2 gene, were able to adapt to this harsh environment, whereas Neanderthal man was unable to do so and became extinct.Keywords: brain / omega-3 / FADS / sapiens / neanderthal Résumé -Évolution du cerveau de l'homme : les rôles clés du DHA (acide gras oméga-3) et du gène de la D6-désaturase. Le processus d'hominisation prend en compte notamment l'élargissement du cerveau. Le développement du capital cognitif des hominidés jusqu'à Homo sapiens est le fait d'une coévolution interactive, itérative et intégrative qui a permis une sélection positive. S'il dépend de nombreux facteurs, trois ensembles ressortent : des mutations génétiques, des ressources alimentaires et des stimulations cognitives et comportementales. À partir des australopithèques, qui ont bénéficié de l'inactivation des gènes GULO et uricase, ainsi que de la bipédie, le cerveau du genre Homo a pu avantageusement se développer. Cette évolution dépend de deux facteurs essentiels. Un facteur déclenchant : un changement climatique progressif. Homo est devenu un consommateur régulier de produits carnés en complément des végétaux et d'insectes. Un facteur stimulant : les mutations sur le gène FADS2 de la D6-désaturase, enzyme clé de la synthèse du DHA et de l'acide sapiénique. Le polymorphisme de ce gène apparaît essentiel pour l'adaptation de Homo à son alimentation et pour son évolution. Il confère un indéniable avantage de productivité en synthèse lipidique (DHA) et peut, en partie, expliquer une sélection positi...

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

Cited by 119 publications

References 259 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

Tracking a complete voltage-sensor cycle with metal-ion bridges

Evolution of the Human Brain: the key roles of DHA (omega-3 fatty acid) and Δ6-desaturase gene

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