Evidence map›Paper›PMID 42390422›Full record

ArticleThe Journal of general physiology2026

Conformational changes upon pore blocker removal reveal conductive states of TMEM16A.

Christina A Stephens, Frank V Marcoline, Christian J Peters, Michael Grabe

Abstract read
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In one paragraph

Article in The Journal of general physiology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

4 authors.

Christina A StephensCardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.ORCID 0000-0001-9382-003X
Frank V MarcolineCardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.ORCID 0000-0002-8842-5470
Christian J PetersDepartment of Anatomy and Cell Biology, University of Illinois College of Medicine, Chicago, IL, USA.ORCID 0000-0002-8794-5394
Michael GrabeCardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.ORCID 0000-0003-3509-5997

Funding

Computational Studies of Sodium SymportersR01GM089740 · NIGMS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GRABE, MICHAEL · 2011 to 2020
$2.8M
Ion permeation, lipid flipping, and membrane remodeling by TMEM16 proteinsR01GM137109 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GRABE, MICHAEL · 2021 to 2024
$1.4M
Neurons of the medial habenula regulate behavioral responses to nicotine in mouseR00DA041500 · NIDA · UNIVERSITY OF ILLINOIS AT CHICAGO · PI PETERS, CHRISTIAN · 2019 to 2021
$747k
High Performance Computer for Computational BiosciencesS10OD021596 · OD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI SALI, ANDREJ · 2016 to 2016
$443k
National Science Foundation 2038436NIDA NIH HHS R00 DA041500NIGMS NIH HHS R01 GM089740NIGMS NIH HHS R01 GM137109NIH HHS 1S10OD020054-011NIH HHS 1S10OD021596NIH HHS R00 DA041500NIH HHS R01GM089740NIH HHS R01 GM137109NIH HHS S10 OD021596University of California, San Francisco
6 · The paper itself

Abstract

TMEM16A is a Ca2+-activated anion channel that provides direct electrical feedback to the plasma membrane in response to intracellular Ca2+. Its conductive state remains unresolved, leaving questions about gating, Cl- permeation, and modulation by Ca2+, depolarization, and lipids. To investigate the open state, we performed molecular dynamics simulations of TMEM16A bound to the putative open-state blocker 1PBC. After inhibitor removal, the putative, pore-lining helix TM4 developed kinks at two sites: an upper site that opens the pore for Cl- permeation and a deeper site causing constriction. A conserved hydrophobic network between TM3 and TM4 persisted in most open structures but separated during extreme dilation, allowing lipids to transiently block the pore. Patch-clamp recordings indicated that the intact network promotes activation. Further simulations yielded >60 Cl- permeation events and a single-channel conductance that matched experiment. Additional electrostatic and kinetic modeling indicated that TMEM16A's transition from outward-rectification to ohmic conductance with increasing Ca2+ results from a weak voltage dependence of binding of Ca2+ ions, which acts cooperatively to open the pore.

Indexed as

Chloride ChannelsNeoplasm ProteinsAnimalsAnoctamin-1CalciumChloridesHumansIon Channel GatingMolecular Dynamics SimulationProtein ConformationThiophenes6-t-butyl-2-(furan-2-carboxamido)-4,5,6,7-tetrahydrobenzo(b)thiophene-3-carboxylic acidANO1 protein, humanAnoctamin-1CalciumChloride ChannelsChloridesNeoplasm ProteinsThiophenes

Identifiers

PMID42390422

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.