title: Different G protein-coupled signaling pathways are involved in alpha granule release from human platelets.
abstract: Alpha granule release plays an important role in propagating a hemostatic response upon platelet activation. We evaluated the ability of various agonists to cause alpha granule release in platelets. Alpha granule release was measured by determining P-selectin surface expression in aspirin-treated washed platelets. ADP-induced P-selectin expression was inhibited both by MRS 2179 (a P2Y1 selective antagonist) and AR-C69931MX (a P2Y12 selective antagonist), suggesting a role for both Galpha(q) and Galpha(i) pathways in ADP-mediated alpha granule release. Consistent with these observations, the combination of serotonin (a Galpha(q) pathway stimulator) and epinephrine (a Galpha(z) pathway stimulator) also caused alpha granule release. Furthermore, U46619-induced P-selectin expression was unaffected by MRS 2179 but was dramatically inhibited by AR-C69931, indicating a dominant role for P2Y12 in U46619-mediated alpha granule release. Additionally, the Galpha(12/13)-stimulating peptide YFLLRNP potentiated alpha granule secretion in combination with either ADP or serotonin/epinephrine costimulation but was unable to induce secretion by itself. Finally, costimulation of the Galpha(i) and Galpha(12/13) pathways resulted in a significant dose-dependent increase in alpha granule release. We conclude that ADP-induced alpha granule release in aspirin-treated platelets occurs through costimulation of Galpha(q) and Galpha(i) signaling pathways. The P2Y12 receptor plays an important role in thromboxane A(2)-mediated alpha granule release, and furthermore activation of Galpha(12/13) and Galpha(q) signaling pathway can cause alpha granule release.
authors.affiliation: Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Quinton
authors.forename: S
authors.initials: S
authors.lastname: Murugappan
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Jin
authors.forename: S P
authors.initials: SP
authors.lastname: Kunapuli
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000378:metabolism; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000502:physiology; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D022142:Secretory Vesicles / Q000378:metabolism*; D015398:Signal Transduction; D013928:Thromboxane A2 / Q000494:pharmacology
chemical_list: D008565:Membrane Proteins; C546382:P2RY1 protein, human; C548576:P2RY12 protein, human; D043562:Receptors, G-Protein-Coupled; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D019206:GTP-Binding Protein alpha Subunits, Gi-Go