Show simple item record

dc.contributor.authorBustos D.
dc.contributor.authorBedoya M.
dc.contributor.authorRamírez D.
dc.contributor.authorConcha G.
dc.contributor.authorZúñiga L.
dc.contributor.authorDecher N.
dc.contributor.authorHernández-rodríguez E.W.
dc.contributor.authorSepúlveda F.V.
dc.contributor.authorMartínez L.
dc.contributor.authorGonzález W.
dc.date.accessioned2020-09-02T22:13:38Z
dc.date.available2020-09-02T22:13:38Z
dc.date.issued2020
dc.identifier10.3390/ijms21020532
dc.identifier.citation21, 2, -
dc.identifier.issn16616596
dc.identifier.urihttps://hdl.handle.net/20.500.12728/3817
dc.descriptionTwo-pore domain potassium (K2P) channels maintain the cell’s background conductance by stabilizing the resting membrane potential. They assemble as dimers possessing four transmembrane helices in each subunit. K2P channels were crystallized in “up” and “down” states. The movements of the pore-lining transmembrane TM4 helix produce the aperture or closure of side fenestrations that connect the lipid membrane with the central cavity. When the TM4 helix is in the up-state, the fenestrations are closed, while they are open in the down-state. It is thought that the fenestration states are related to the activity of K2P channels and the opening of the channels preferentially occurs from the up-state. TASK-2, a member of the TALK subfamily of K2P channels, is opened by intracellular alkalization leading the deprotonation of the K245 residue at the end of the TM4 helix. This charge neutralization of K245 could be sensitive or coupled to the fenestration state. Here, we describe the relationship between the states of the intramembrane fenestrations and K245 residue in TASK-2 channel. By using molecular modeling and simulations, we show that the protonated state of K245 (K245+) favors the open fenestration state and, symmetrically, that the open fenestration state favors the protonated state of the lysine residue. We show that the channel can be completely blocked by Prozac, which is known to induce fenestration opening in TREK-2. K245 protonation and fenestration aperture have an additive effect on the conductance of the channel. The opening of the fenestrations with K245+ increases the entrance of lipids into the selectivity filter, blocking the channel. At the same time, the protonation of K245 introduces electrostatic potential energy barriers to ion entrance. We computed the free energy profiles of ion penetration into the channel in different fenestration and K245 protonation states, to show that the effects of the two transformations are summed up, leading to maximum channel blocking. Estimated rates of ion transport are in qualitative agreement with experimental results and support the hypothesis that the most important barrier for ion transport under K245+ and open fenestration conditions is the entrance of the ions into the channel. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
dc.language.isoen
dc.publisherMDPI AG
dc.subjectFunction relationships
dc.subjectHomology modeling
dc.subjectK2P channels
dc.subjectModeling of protein dynamics
dc.subjectStructure
dc.subjectTASK-2 channels
dc.subjection channel
dc.subjectpotassium channel
dc.subjectTASK 2 channel
dc.subjecttwo pore domain potassium channel
dc.subjectunclassified drug
dc.subjectalkalinization
dc.subjectArticle
dc.subjectcellular distribution
dc.subjectdeprotonation
dc.subjection transport
dc.subjectlipid membrane
dc.subjectmembrane conductance
dc.subjectmembrane electrophysiology
dc.subjectmolecular dynamics
dc.subjectmolecular model
dc.subjectpH measurement
dc.subjectprotein expression
dc.subjectprotein interaction
dc.subjectprotein structure
dc.subjectprotonation
dc.subjectsequence homology
dc.subjectstatic electricity
dc.titleElucidating the structural basis of the intracellular ph sensing mechanism of TASK-2 K2P channels
dc.typeArticle


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record