Evidence map›Paper›PMID 41371222›Full record

ArticleMolecular cell2025

Puromycin-sensitive aminopeptidase acts as an inhibitory auxiliary subunit of volume-regulated anion channels and regulates cGAMP transport.

Wenqiang Zheng, Tatsuya Hagino, Hao Wang, Henry Yi Cheng, Nicholas Koylass, Kevin Hong Chen, Haobo Wang, Sepehr Mani, Anish Kumar Mondal, Edward C Twomey and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing 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

2 citing papers in PubMed.

  1. Article
  2. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

11 authors.

Wenqiang ZhengDepartment of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Tatsuya HaginoDepartment of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Hao WangDepartment of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Henry Yi ChengDepartment of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nicholas KoylassDepartment of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Kevin Hong ChenDepartment of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Haobo WangDepartment of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sepehr ManiDepartment of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Anish Kumar MondalDepartment of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Edward C TwomeyDepartment of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; XDBio Cross Disciplinary Graduate Program in Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Zhaozhu QiuDepartment of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: zhaozhu@jhmi.edu.

Funding

Molecular Identity and Physiological Function of Novel Chloride ChannelsR35GM124824 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI Zhaozhu Qiu · 2017 to 2026
$4.8M
Validation of a new large-pore channel as a novel target for neuropathic painRF1NS134549 · NINDS · JOHNS HOPKINS UNIVERSITY · PI Yun Guan, Zhaozhu Qiu · 2023 to 2026
$3.4M
Cell Swelling-Activated Chloride Channel in Ischemic StrokeR01NS118014 · NINDS · JOHNS HOPKINS UNIVERSITY · PI QIU, ZHAOZHU · 2020 to 2024
$2.6M
Ligand Gated Ion Channels Across Time and SpaceR35GM154904 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI Edward C Twomey · 2024 to 2026
$1.2M
NIGMS NIH HHS R35 GM124824NIGMS NIH HHS R35 GM154904NINDS NIH HHS R01 NS118014NINDS NIH HHS RF1 NS134549
6 · The paper itself

Abstract

Volume-regulated anion channels (VRACs) are large-pore channels expressed in most vertebrate cells and are critical for cell volume regulation and autocrine/paracrine signaling. Here, we identify the ubiquitously expressed puromycin-sensitive aminopeptidase (PSA) as a binding partner of the obligatory VRAC subunit SWELL1 (also known as LRRC8A) and determine the cryo-electron microscopy structure of the SWELL1-PSA complex. Three PSA molecules bind a single SWELL1 hexamer, coupling adjacent leucine-rich repeat (LRR) domains into local dimers. Functionally, PSA overexpression suppresses VRAC activation, whereas PSA deletion dramatically elevates basal channel activity. Notably, PSA's modulation of VRACs requires physical binding but not aminopeptidase activity, indicating a structural mechanism. Our findings identify PSA as an auxiliary subunit of VRACs, highlight the role of intracellular LRR domains in allosteric channel gating, and suggest a strategy to tune VRAC function in diverse physiological contexts, including 2'3'-cyclic GMP-AMP (cGAMP) transport and downstream stimulator of interferon genes (STING) signaling.

Indexed as

AminopeptidasesIon ChannelsMembrane ProteinsAnimalsCryoelectron MicroscopyHEK293 CellsHumansIon Channel GatingMiceNucleotides, CyclicProtein BindingAminopeptidasescyclic guanosine monophosphate-adenosine monophosphateIon ChannelsLRRC8A protein, humanMembrane ProteinsNucleotides, CycliccGAMPLRRC8LRRC8ANPEPPSSTINGSWELL1

Identifiers

PMID41371222
PMCPMC12698191

What OpenQuestion holds

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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.