title: P2X1-initiated p38 signalling enhances thromboxane A2-induced platelet secretion and aggregation.
abstract: 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<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 in combination, and by P2X1 pre-desensitisation with α,β-Me-ATP. U46619 caused rapid and reversible P2X1-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, P2X1 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.
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
authors.forename: P
authors.initials: P
authors.lastname: Liu
authors.forename: L
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Nailin Li, MD, PhD, FAHA, Karolinska Institute, Department of Medicine-Solna, Clinical Pharmacology Unit, Karolinska University Hospital-Solna, SE-171 76 Stockholm, SWEDEN, E-mail: Nailin.Li@ki.se.
authors.forename: N
authors.initials: N
authors.lastname: Li
authors.affiliation: Hu Hu, MD, PhD, Department of Pathology & Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China, E-mail: huhu@zju.edu.cn.
authors.forename: H
authors.initials: H
authors.lastname: Hu
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000328:Adult; D001557:Benzenesulfonates / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D058474:Receptors, Purinergic P2X1 / Q000378:metabolism*; D013928:Thromboxane A2 / Q000378:metabolism*; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: C110258:4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate); D001557:Benzenesulfonates; D007093:Imidazoles; D019007:P-Selectin; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D058474:Receptors, Purinergic P2X1; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: ATP; P2X1; Platelets; p38; thromboxane A2