{"doi":"10.1101/2024.09.26.615233","title":"LRRC8 complexes are adenosine nucleotide release channels regulating platelet activation and arterial thrombosis","abstract":"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, ATP secretion and calcium mobilization. MK-specific LRRC8A cKO mice have reduced arteriolar thrombus formation and prolonged arterial thrombosis without affecting bleeding times. Mechanistically, platelet LRRC8A mediates swell-induced ATP/ADP release to amplify agonist-stimulated calcium and PI3K-AKT signaling via P2X1, P2Y 1 and P2Y 12 receptors. 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/ADP release channel in platelets which regulates platelet function and thrombosis, providing a proof-of-concept for a novel anti-thrombotic drug target.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":503938,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9536,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1354519,"name":"Ryan Mikami","orcid":null,"position":1,"is_corresponding":false},{"id":1354165,"name":"Ashutosh Kumar","orcid":"0000-0001-6938-619X","position":2,"is_corresponding":false},{"id":1062240,"name":"Gavriel Brown","orcid":null,"position":3,"is_corresponding":false},{"id":441567,"name":"Tarek Mohamed Abd El‐Aziz","orcid":"0000-0002-3441-9673","position":4,"is_corresponding":false},{"id":1354166,"name":"Yonghui Zhao","orcid":"0000-0002-4382-6334","position":5,"is_corresponding":false},{"id":1106186,"name":"Nihil Abraham","orcid":null,"position":6,"is_corresponding":false},{"id":1354167,"name":"Chloe Meyer","orcid":"0009-0000-9679-7795","position":7,"is_corresponding":false},{"id":874848,"name":"Abigail Ajanel","orcid":"0000-0002-4601-3769","position":8,"is_corresponding":false},{"id":303252,"name":"Litao Xie","orcid":null,"position":9,"is_corresponding":false},{"id":989573,"name":"Katrina Ashworth","orcid":"0000-0001-7862-6503","position":10,"is_corresponding":false},{"id":320563,"name":"Juan Hong","orcid":"0000-0002-2542-960X","position":11,"is_corresponding":false},{"id":748569,"name":"Haixia Zhang","orcid":"0000-0003-1453-6503","position":12,"is_corresponding":false},{"id":687995,"name":"Tripti Kumari","orcid":"0000-0002-2638-0705","position":13,"is_corresponding":false},{"id":565201,"name":"Adam Balutowski","orcid":null,"position":14,"is_corresponding":false},{"id":575017,"name":"Alice Liu","orcid":"0000-0003-4813-836X","position":15,"is_corresponding":false},{"id":429897,"name":"David Bark","orcid":"0000-0002-9865-6176","position":16,"is_corresponding":false},{"id":1354520,"name":"Vinayak K. 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