LRRC8 complexes are ATP release channels that regulate platelet activation and arterial thrombosis.

Publication Type	Academic Article
Authors	Tranter J, Mikami R, Kumar A, Brown G, Abd El-Aziz T, Zhao Y, Arullampalam P, Ashworth K, Jha V, Abraham N, Meyer C, Ajanel A, Xie L, Feng Y, Hong J, Zhang H, Kumari T, Balutowski A, Liu A, Bark D, Nair V, Lasky N, Stitziel N, Lerner D, Campbell R, Di Paola J, Cho J, Sah R
Journal	Blood
Volume	146
Issue	9
Pagination	1110-1126
Date Published	08/28/2025
ISSN	1528-0020
Keywords	Adenosine Triphosphate, Platelet Activation, Blood Platelets, Thrombosis, Membrane Proteins
Abstract	Platelet shape and volume changes are early mechanical events contributing to platelet activation and thrombosis. Here, we identify single-nucleotide polymorphisms in leucine-rich repeat-containing 8 (LRRC8) protein subunits that form the volume-regulated anion channel (VRAC), which are independently associated with altered mean platelet volume. LRRC8A is required for functional VRAC in megakaryocytes (MKs) and regulates platelet volume; adhesion; and agonist-stimulated activation, aggregation, adenosine triphosphate (ATP) secretion, and calcium mobilization. MK-specific LRRC8A conditional knockout mice have reduced laser injury-induced cremaster arteriolar thrombus formation and prolonged FeCl3 induced carotid arterial thrombosis without prolonged bleeding times. Mechanistically, platelet LRRC8A mediates swell-induced cytosolic ATP release to amplify agonist-stimulated calcium-phosphoinositide 3-kinase-protein kinase B signaling. Small-molecule LRRC8 channel inhibitors recapitulate defects observed in LRRC8A-null platelets in vitro and in vivo. These studies identify the mechanoresponsive LRRC8 channel complex as an ATP release channel in platelets, which positively regulates platelet function and thrombosis, providing a proof of concept for a novel antithrombotic drug target.
DOI	10.1182/blood.2024026667
PubMed ID	40540747
PubMed Central ID	PMC12755129