{"doi":"10.1160/th13-09-0726","title":"P2X1-initiated p38 signalling enhances thromboxane A2-induced platelet secretion and aggregation","abstract":"<jats:title>Summary</jats:title><jats:p>ATP released by activated platelets can serve as a positive feedback machinery to amplify platelet responses by activating P2X1 receptors. It has, however, not been defined how P2X1 activities influence thromboxane A2 (TXA2)-stimulated platelet functional responses. Our aim was to elaborate the molecular mechanisms of P2X1 engagements in TXA2-induced platelet secretion and aggregation. P2X1 inhibition by 1 µM NF449 inhibited platelet P-selectin expression induced by a low concentration of the TXA2 analogue U46619 (0.3 µM) (32.0 ± 2.0% vs 43.4 ± 3.0%; n=5; p&lt;0.05). p38 inhibition by SB203580, but not ERK inhibition by U0126, elicited a similar inhibition by NF499. The combination of NF449 and SB203580 provided, however, no additive effects. U46619-induced platelet aggregation was similarly decreased by NF449 and SB203580 alone or incombination, and by P2×1 pre-desensitisation with α,β-Me-ATP. U46619 caused rapid and reversible P2×1-dependent p38 phosphorylation. However, the P2X1-p38 pathway mainly enhanced mild platelet activation by U46619, because α,β-Me-ATP supplementation or p38 blockade had no effect on intense platelet activation induced by a higher concentration of U46619 (3 µM). In conclusion, P2×1 activation, via p38 signalling, potentiates platelet activation initiated by low doses of U46619. Hence, the P2X1-induced p38 signalling promotes more robust platelet activation in response to mild platelet stimuli.</jats:p>","journal":"Thrombosis and Haemostasis","year":2014,"id":624353,"datarank":0.41588830833596724,"base_score":2.772588722239781,"endowment":2.772588722239781,"self_citation_contribution":0.41588830833596724,"citation_network_contribution":0.0,"self_endowment_contribution":0.41588830833596724,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":192868,"name":"Pu Liu","orcid":null,"position":1,"is_corresponding":false},{"id":1614003,"name":"Linjing Zhu","orcid":null,"position":2,"is_corresponding":false},{"id":1614005,"name":"Nailin Li","orcid":null,"position":3,"is_corresponding":false},{"id":1570797,"name":"Hu Hu","orcid":"0000-0002-0009-8218","position":4,"is_corresponding":false},{"id":1606596,"name":"Zhangsen Huang","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"P2X1-initiated p38 signalling enhances thromboxane A2-induced platelet secretion and aggregation","abstract":"<jats:title>Summary</jats:title><jats:p>ATP released by activated platelets can serve as a positive feedback machinery to amplify platelet responses by activating P2X1 receptors. It has, however, not been defined how P2X1 activities influence thromboxane A2 (TXA2)-stimulated platelet functional responses. Our aim was to elaborate the molecular mechanisms of P2X1 engagements in TXA2-induced platelet secretion and aggregation. P2X1 inhibition by 1 µM NF449 inhibited platelet P-selectin expression induced by a low concentration of the TXA2 analogue U46619 (0.3 µM) (32.0 ± 2.0% vs 43.4 ± 3.0%; n=5; p&lt;0.05). p38 inhibition by SB203580, but not ERK inhibition by U0126, elicited a similar inhibition by NF499. The combination of NF449 and SB203580 provided, however, no additive effects. U46619-induced platelet aggregation was similarly decreased by NF449 and SB203580 alone or incombination, and by P2×1 pre-desensitisation with α,β-Me-ATP. U46619 caused rapid and reversible P2×1-dependent p38 phosphorylation. However, the P2X1-p38 pathway mainly enhanced mild platelet activation by U46619, because α,β-Me-ATP supplementation or p38 blockade had no effect on intense platelet activation induced by a higher concentration of U46619 (3 µM). In conclusion, P2×1 activation, via p38 signalling, potentiates platelet activation initiated by low doses of U46619. Hence, the P2X1-induced p38 signalling promotes more robust platelet activation in response to mild platelet stimuli.</jats:p>","is_dataset_classified":null,"base_score":2.772588722239781,"endowment":2.772588722239781,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"24633352","pmcid":null,"openalex_id":"https://openalex.org/W2078000974","authors":[],"funders":[{"funder_name":"National Natural Science Foundation of China","grant_id":"30700267, 81170478","title":null},{"funder_name":"Swedish Research Council","grant_id":"unidentified","title":"unidentified"}],"total_grants":2,"fwci":0.7762,"citation_percentile":0.72747901,"influential_citations":1,"citation_trend":[{"year":2015,"count":2},{"year":2016,"count":1},{"year":2018,"count":2},{"year":2019,"count":1},{"year":2020,"count":2},{"year":2021,"count":1},{"year":2022,"count":1},{"year":2023,"count":3},{"year":2025,"count":1},{"year":2026,"count":1}],"oa_status":"closed","license":null,"oa_locations":[{"url":"http://www.thieme-connect.de/products/ejournals/pdf/10.1160/TH13-09-0726.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1160/th13-09-0726","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/24633352","host_type":"repository"},{"url":"https://dx.doi.org/10.1160/th13-09-0726","host_type":""}],"fields_of_study":["Adenosine and Purinergic Signaling","Platelet Disorders and Treatments","Antiplatelet Therapy and Cardiovascular Diseases","Medicine","Chemistry","Biology","0301 basic medicine","03 medical and health sciences","0302 clinical medicine","15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid","Adult","Benzenesulfonates","Blood Platelets","Cell Degranulation","Cells, Cultured","Female","Gene Expression Regulation","Humans","Imidazoles","MAP Kinase Signaling System","Male","P-Selectin","Phosphorylation","Platelet Aggregation","Purinergic P2X Receptor Antagonists","Pyridines","Receptors, Purinergic P2X1","Thromboxane A2","Young Adult","p38 Mitogen-Activated Protein Kinases"],"mesh_terms":["Adult","Benzenesulfonates","Blood Platelets","Cells, Cultured","Female","Gene Expression Regulation","Humans","Imidazoles","Male","Phosphorylation","Platelet Aggregation","Pyridines","Thromboxane A2","Cell Degranulation","P-Selectin","15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid","MAP Kinase Signaling System","p38 Mitogen-Activated Protein Kinases","Young Adult","Receptors, Purinergic P2X1","Purinergic P2X Receptor Antagonists"],"keywords":["Thromboxane A2","Platelet activation","Platelet","Thromboxane","p38 mitogen-activated protein kinases","Chemistry","Phosphorylation","Cell biology","Pharmacology","Endocrinology","Internal medicine","Medicine","MAPK/ERK pathway","Biology","Biochemistry","Adult","Blood Platelets","Male","Platelet Aggregation","Purinergic P2X Receptor Antagonists","MAP Kinase Signaling System","Pyridines","Benzenesulfonates","Imidazoles","Cell Degranulation","Receptors, Purinergic P2X1","P-Selectin","Young Adult","Gene Expression Regulation","15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid","Humans","Female","Cells, Cultured","ATP","P2X1","Platelets","p38"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-04T03:32:35.852241Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}