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ATP-release pannexin channels are gated by lysophospholipids.

Erik Henze | Russell N Burkhardt | Bennett William Fox | Tyler J Schwertfeger | Eric Gelsleichter | Kevin Michalski | Lydia Kramer | Margret Lenfest | Jordyn M Boesch | Hening Lin | Frank C Schroeder | Toshimitsu Kawate
eLife | 2025

In addition to its role as cellular energy currency, adenosine triphosphate (ATP) serves as an extracellular messenger that mediates diverse cell-to-cell communication. Compelling evidence supports that ATP is released from cells through pannexins, a family of membrane proteins that form heptameric large-pore channels. However, the activation mechanisms that trigger ATP release by pannexins remain poorly understood. Here, we discover lysophospholipids as endogenous pannexin activators, using activity-guided fractionation of mouse tissue extracts combined with untargeted metabolomics and electrophysiology. We show that lysophospholipids directly and reversibly activate pannexins in the absence of other proteins. Secretomics experiments reveal that lysophospholipid-activated pannexin 1 leads to the release of not only ATP but also other signaling metabolites, such as 5'-methylthioadenosine, which is important for immunomodulation. We also demonstrate that lysophospholipids activate endogenous pannexin 1 in human monocytes, leading to the release of IL-1β through inflammasome activation. Our results provide a connection between lipid metabolism and purinergic signaling, both of which play major roles in immune responses.

Pubmed ID: 40309905

Associated grants

  • Agency: National Science Foundation,
    Id: DBI1659534
  • Agency: NIH HHS, United States
    Id: T32GM008267
  • Agency: NIH HHS, United States
    Id: R01GM114379
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK107451
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM114379
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM008267
  • Agency: NIGMS NIH HHS, United States
    Id: R35 GM131877
  • Agency: NIH HHS, United States
    Id: R01DK107451
  • Agency: NIH HHS, United States
    Id: R35GM131877

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This is a list of tools and resources that we have found mentioned in this publication.


ATCC (tool)

RRID:SCR_001672

Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.

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RRID:SCR_002037

Non-profit plasmid repository dedicated to helping scientists around the world share high-quality plasmids. Facilitates archiving and distributing DNA-based research reagents and associated data to scientists worldwide. Repository contains over 65,000 plasmids, including special collections on CRISPR, fluorescent proteins, and ready-to-use viral preparations. There is no cost for scientists to deposit plasmids, which saves time and money associated with shipping plasmids themselves. All plasmids are fully sequenced for validation and sequencing data is openly available. We handle the appropriate Material Transfer Agreements (MTA) with institutions, facilitating open exchange and offering intellectual property and liability protection for depositing scientists. Furthermore, we curate free educational resources for the scientific community including a blog, eBooks, video protocols, and detailed molecular biology resources.

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RRID:SCR_002760

NIH genetic sequence database that provides annotated collection of all publicly available DNA sequences for almost 280 000 formally described species (Jan 2014) .These sequences are obtained primarily through submissions from individual laboratories and batch submissions from large-scale sequencing projects, including whole-genome shotgun (WGS) and environmental sampling projects. Most submissions are made using web-based BankIt or standalone Sequin programs, and GenBank staff assigns accession numbers upon data receipt. It is part of International Nucleotide Sequence Database Collaboration and daily data exchange with European Nucleotide Archive (ENA) and DNA Data Bank of Japan (DDBJ) ensures worldwide coverage. GenBank is accessible through NCBI Entrez retrieval system, which integrates data from major DNA and protein sequence databases along with taxonomy, genome, mapping, protein structure and domain information, and biomedical journal literature via PubMed. BLAST provides sequence similarity searches of GenBank and other sequence databases. Complete bimonthly releases and daily updates of GenBank database are available by FTP.

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American chemical, life science and biotechnology company owned by Merck KGaA. Merger of Sigma Chemical Company and Aldrich Chemical Company. Provides organic and inorganic chemicals, building blocks, reagents, advanced materials and stable isotopes for chemical synthesis, medicinal chemistry and materials science, antibiotics, buffers, carbohydrates, enzymes, forensic tools, hematology and histology, nucleotides, proteins, peptides, amino acids and their derivatives.

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RRID:SCR_011323

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RRID:SCR_012931

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RRID:SCR_025461

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RRID:IMSR_JAX:000664

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RRID:AB_2800167

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RRID:CVCL_A785

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