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Conformational Changes during Potassium-Channel Gating
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Voltage-gated ion channels have a paramount importance in many physiological processes such as cell-to-cell communication, action potential-propagation, and cell motility. Voltage-gated ion channels are characterized by their ability to sense membrane voltage and to greatly change channel activity in response to small changes in the voltage. The ability to sense voltage resides in the four voltage-sensor domains (VSDs) surrounding the central ion-conducting pore. Membrane depolarization causes the inside of the membrane to become positively charged, electrostatically repelling the positively charged fourth transmembrane segment (S4), or voltage sensor, in the VSD, causing the voltage sensor to move outwards. This motion provides necessary energy to open the pore and allow ion conductivity. Prolonged channel activation leads to alterations in the selectivity filter which cease ion conductivity, in a process called slow inactivation. In this thesis, we investigated the movement of S4 during activation of the channel. We also studied the communication between the four subunits during activation as well as the communication between the pore domain and VSD during slow inactivation.

We have shown that voltage sensors move approximately 12 Å outwards during activation. The positively charged amino acid residues in S4 create temporary salt bridges with negative counter-charges in the other segments of the VSD as it moves through a membrane. We have also shown that the movement of one of the four voltage sensors can affect the movement of the neighboring voltage sensors. When at least one voltage sensor has moved to an up-position, it stabilizes other voltage sensors in the up-position, increasing the energy required for the voltage sensor to return to the down position.

We have also shown reciprocal communication between the pore domain and the VSDs. Alterations in the VSD or the interface between the pore and the VSD cause changes in the rate of slow inactivation. Likewise, modifications in the pore domain cause changes to the voltage-sensor movement. This indicates communication between the pore and the VSD during slow inactivation.

The information from our work could be used to find new approaches when designing channel-modifying drugs for the treatment of diseases caused by increased neuronal excitability, such as chronic pain and epilepsy.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. , p. 69
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1614
Keywords [en]
ion-channel, electrophysiology, neuron
Keywords [sv]
Jonkanal, neurologi, elektrofysiologi, neuron, aktionspotential
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-146967DOI: 10.3384/diss.diva-146967ISBN: 9789176853382 (print)OAI: oai:DiVA.org:liu-146967DiVA, id: diva2:1196098
Public defence
2018-05-09, Berzeliussalen, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2018-04-09 Created: 2018-04-09 Last updated: 2018-04-16Bibliographically approved
List of papers
1. Tracking a complete voltage-sensor cycle with metal-ion bridges
Open this publication in new window or tab >>Tracking a complete voltage-sensor cycle with metal-ion bridges
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2012 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 22, p. 8552-8557Article in journal (Refereed) Published
Abstract [en]

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 angstrom 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.

Place, publisher, year, edition, pages
National Academy of Sciences, 2012
Keywords
electrophysiology, inactivation, Xenopus oocytes, voltage clamp, conformational transition
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-78812 (URN)10.1073/pnas.1116938109 (DOI)000304881700044 ()
Note

Funding Agencies|Swedish Research Council||Swedish Heart-Lung Foundation||Swedish Brain Foundation||County Council of Ostergotland||Queen Silvias Anniversary Foundation||King Gustaf V and Queen Victorias Freemasons Foundation||Stina and Birger Johanssons Foundation||Swedish Society for Medical Research||Swedish Foundation for Strategic Research||European Research Council||

Available from: 2012-06-21 Created: 2012-06-21 Last updated: 2018-04-09
2. Reciprocal voltage sensor-to-pore coupling leads to potassium channel C-type inactivation
Open this publication in new window or tab >>Reciprocal voltage sensor-to-pore coupling leads to potassium channel C-type inactivation
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 27562Article in journal (Refereed) Published
Abstract [en]

Voltage-gated potassium channels open at depolarized membrane voltages. A prolonged depolarization causes a rearrangement of the selectivity filter which terminates the conduction of ions - a process called slow or C-type inactivation. How structural rearrangements in the voltage-sensor domain (VSD) cause alteration in the selectivity filter, and vice versa, are not fully understood. We show that pulling the pore domain of the Shaker potassium channel towards the VSD by a Cd2+ bridge accelerates C-type inactivation. Molecular dynamics simulations show that such pulling widens the selectivity filter and disrupts the K+ coordination, a hallmark for C-type inactivation. An engineered Cd2+ bridge within the VSD also affect C-type inactivation. Conversely, a pore domain mutation affects VSD gating-charge movement. Finally, C-type inactivation is caused by the concerted action of distant amino acid residues in the pore domain. All together, these data suggest a reciprocal communication between the pore domain and the VSD in the extracellular portion of the channel.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Structural Biology
Identifiers
urn:nbn:se:liu:diva-130064 (URN)10.1038/srep27562 (DOI)000377343800001 ()27278891 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Brain Foundation; Swedish Heart-Lung Foundation; Swedish e-Science Research Center; Foundation Blanceflor Boncompagni Ludovisi, nee Bildt

Available from: 2016-07-06 Created: 2016-07-06 Last updated: 2018-04-09

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Renhorn, Jakob

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