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Reciprocal voltage sensor-to-pore coupling leads to potassium channel C-type inactivation
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
KTH Royal Institute Technology, Sweden.
Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
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2016 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikel-id 27562Artikel i tidskrift (Refereegranskat) Published
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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.

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NATURE PUBLISHING GROUP , 2016. Vol. 6, artikel-id 27562
Nationell ämneskategori
Strukturbiologi
Identifikatorer
URN: urn:nbn:se:liu:diva-130064DOI: 10.1038/srep27562ISI: 000377343800001PubMedID: 27278891OAI: oai:DiVA.org:liu-130064DiVA, id: diva2:947007
Anmärkning

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

Tillgänglig från: 2016-07-06 Skapad: 2016-07-06 Senast uppdaterad: 2018-04-09
Ingår i avhandling
1. Conformational Changes during Potassium-Channel Gating
Öppna denna publikation i ny flik eller fönster >>Conformational Changes during Potassium-Channel Gating
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2018. s. 69
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1614
Nyckelord
ion-channel, electrophysiology, neuron, Jonkanal, neurologi, elektrofysiologi, neuron, aktionspotential
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
urn:nbn:se:liu:diva-146967 (URN)10.3384/diss.diva-146967 (DOI)9789176853382 (ISBN)
Disputation
2018-05-09, Berzeliussalen, Campus US, Linköping, 13:00 (Engelska)
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Handledare
Tillgänglig från: 2018-04-09 Skapad: 2018-04-09 Senast uppdaterad: 2018-04-16Bibliografiskt granskad

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Conti, LucaRenhorn, JakobLiin, SaraElinder, Fredrik

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