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Phospholipid flippases ATP8A1 and ATP8A2 regulate GABA<sub>A</sub> receptor trafficking through distinct mechanisms in hippocampal neurons.

Overview

Authors: Muneyuki Kawase1, Shu Tokunaga1, Yuta Umemura1, Hossam H Shawki2, Jumpei Omi3, Ayana Hoshiai1, Tomoha Ohshima1, Tsuzumi Nakajima1, Takao Kohno1, Takashi Sakurai4, Junken Aoki3, Hisashi Oishi2, Mitsuharu Hattori1
ORCID iDs: Mitsuharu Hattori
  1. Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan
  2. Department of Comparative and Experimental Medicine, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-0002, Japan
  3. Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
  4. Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
Institutions: Nagoya City University (Japan); The University of Tokyo (Japan); Juntendo University (Japan)
Journal: iScience, volume 29, issue 7, article 116626
Dates: received 7 November 2025; accepted 15 June 2026; published online 30 June 2026
Type: Research article · Language: English
License: CC BY-NC
Identifiers: DOI 10.1016/j.isci.2026.116626 · PMID 42491662 · PMCID PMC13378359 · OpenAlex W7166710606
Open access: gold, a free copy (OpenAlex)
Status: code on request
Categories: mouse (organism), cellular / molecular (subfield)
Methods: Spectral & time-frequency, Statistics
Keywords: Phospholipid flippase, inhibitory synapse, GABAA receptor, phosphatidylserine, dynamin
Topic: Lipid Membrane Structure and Behavior (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: Japan Science and Technology Agency; Japan Society for the Promotion of Science; Nagoya City University; Terumo Foundation for Life Sciences and Arts
Citations: not cited yet (Europe PMC); 62 references in the paper
Research resources: Rabbit polyclonal anti-ATP8A1 RRID:AB_10734587, Rabbit polyclonal anti-GFAP RRID:AB_10980769, RRID:AB_11012142, RRID:AB_11212678, RRID:AB_141607, RRID:AB_141633, RRID:AB_141637, Rabbit polyclonal anti-dynamin2 RRID:AB_2093679, RRID:AB_2109419, RRID:AB_2534117, RRID:AB_2535792, RRID:AB_2535794, RRID:AB_2535795, RRID:AB_309747, Rat monoclonal anti-HA (clone 3F10) RRID:AB_390918, RRID:AB_476692, Mouse monoclonal anti-MAP2 (clone AP-20) RRID:AB_477171, RRID:AB_627670, Mouse monoclonal anti-PSD95 (clone 7E3) RRID:AB_628114, RRID:AB_772191, RRID:AB_772193, Rabbit polyclonal anti-Iba1 RRID:AB_839504, Guinea pig polyclonal anti-VGAT RRID:AB_887873, Guinea pig polyclonal anti-VGLUT1 RRID:AB_887878, Fiji/ImageJ RRID:SCR_002285, Graphpad Prism 10 RRID:SCR_002798, MassLynx RRID:SCR_014271, StepOnePlus RRID:SCR_015805, Zeiss LSM 800 with Airyscan Microscope RRID:SCR_015963, BZ-X710 fluorescent microscope RRID:SCR_017202, Xevo TQ-XS RRID:SCR_018510, Trans-Blot SD Semi-Dry Transfer Cell RRID:SCR_019036, Zeiss LSM 900 with Airyscan 2 RRID:SCR_022263, CRISPick RRID:SCR_025148, CM1850 Cryostat RRID:SCR_025401, Optima MAX-XP RRID:SCR_025704, Acquity UPLC RRID:SCR_027039

Abstract

Phospholipid asymmetry in cellular membranes is maintained by flippases. ATP8A1 and ATP8A2 are the principal flippases of phosphatidylserine (PS) in the mammalian nervous system; however, their specific physiological roles and potential functional redundancy remain incompletely characterized. Here, we show that ATP8A1/ATP8A2 double-knockout mice displayed more severe growth retardation than ATP8A2 knockout mice, indicating that ATP8A1 and ATP8A2 play redundant roles. In hippocampal neurons, ATP8A2 was highly enriched at inhibitory post-synapses. Surface biotinylation assays revealed increased surface GABAA receptor levels of hippocampal neurons deficient for ATP8A1 or ATP8A2. Mechanistically, our data support a model in which ATP8A2, but not ATP8A1, regulates local membrane lipid asymmetry, thereby facilitating dynamin2 recruitment and promoting GABAA receptor endocytosis. Collectively, ATP8A1 and ATP8A2 share overlapping roles in postnatal growth, while they contribute to neural function by modulating inhibitory synaptic transmission through distinct mechanisms.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none (its code is available on request), so it has no map.

Data

Datasets cited

Data and code availability

All data supporting the findings of this study are available in the article and in the supplemental information and/or from the lead contact upon request. Unprocessed results have been deposited in Mendeley Data (https://doi.org/10.17632/8tv7ryv39d.1).

This study did not generate original code.

Any additional information required to reanalyze the data reported will be shared by the lead contact upon request.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

  • Authors: added Mitsuharu Hattori (0000-0002-0503-4969); removed Mitsuharu Hattori

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 5 keywords, 4 funders, 62 references, 37 RRIDs.

Cite

This paper

Kawase, M., Tokunaga, S., Umemura, Y., Shawki, H. H., Omi, J., Hoshiai, A., Ohshima, T., Nakajima, T., Kohno, T., Sakurai, T., Aoki, J., Oishi, H., & Hattori, M. (2026). Phospholipid flippases ATP8A1 and ATP8A2 regulate GABA<sub>A</sub> receptor trafficking through distinct mechanisms in hippocampal neurons. iScience, 29(7), 116626. https://doi.org/10.1016/j.isci.2026.116626

BibTeX

@article{kawase2026phospholipid,
author = {Kawase, Muneyuki and Tokunaga, Shu and Umemura, Yuta and Shawki, Hossam H and Omi, Jumpei and Hoshiai, Ayana and Ohshima, Tomoha and Nakajima, Tsuzumi and Kohno, Takao and Sakurai, Takashi and Aoki, Junken and Oishi, Hisashi and Hattori, Mitsuharu},
title = {{Phospholipid flippases ATP8A1 and ATP8A2 regulate GABA\<sub\>A\</sub\> receptor trafficking through distinct mechanisms in hippocampal neurons}},
journal = {iScience},
year = {2026},
month = jun,
volume = {29},
number = {7},
pages = {116626},
publisher = {Elsevier},
issn = {2589-0042},
doi = {10.1016/j.isci.2026.116626},
url = {https://doi.org/10.1016/j.isci.2026.116626},
pmid = {42491662},
pmcid = {PMC13378359}
}

RIS

TY - JOUR
AU - Kawase, Muneyuki
AU - Tokunaga, Shu
AU - Umemura, Yuta
AU - Shawki, Hossam H
AU - Omi, Jumpei
AU - Hoshiai, Ayana
AU - Ohshima, Tomoha
AU - Nakajima, Tsuzumi
AU - Kohno, Takao
AU - Sakurai, Takashi
AU - Aoki, Junken
AU - Oishi, Hisashi
AU - Hattori, Mitsuharu
TI - Phospholipid flippases ATP8A1 and ATP8A2 regulate GABA<sub>A</sub> receptor trafficking through distinct mechanisms in hippocampal neurons
T2 - iScience
J2 - iScience
PY - 2026
DA - 2026/06/30
VL - 29
IS - 7
SP - 116626
SN - 2589-0042
PB - Elsevier
DO - 10.1016/j.isci.2026.116626
UR - https://doi.org/10.1016/j.isci.2026.116626
LA - en
ER -

CSL-JSON

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"container-title": "iScience",
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