title: AlphaIIbbeta3-mediated outside-in signaling induced by the agonist peptide LSARLAF utilizes ADP and thromboxane A2 receptors to cause alpha-granule secretion by platelets.
abstract: The peptide LSARLAF (LSA) causes alphaIIbbeta3-dependent platelet activation that results in alpha-granule secretion and aggregation. LSARLAF-induced, alphaIIbbeta3-mediated outside-in signaling causing alpha-granule secretion and platelet aggregation was studied using washed mouse platelets. ADP receptor antagonists, enzyme inhibitors, normal platelets and platelets from mice that lack either Galphaq or thromboxane (Tx) A2 receptors were used for this investigation. The results demonstrate that LSA-induced alphaIIbbeta3-mediated signaling producing aggregation of washed platelets is mediated through the release of ADP and thromboxane, which cause alpha-granule release by mediating their effects though Galphaq and/or Gi depending on the level of LSA used to activate the platelets. Specifically, alphaIIbbeta3 elicited aggregation of washed platelets in response to a low level of LSA requires signaling through the ADP receptor P2Y1 and Galphaq, and the ADP receptor P2Y12 and Gi as well as TxA2 receptors. However, this aggregation is independent of Galphaq and TxA2 signaling in response to high LSA concentrations, but is dependent on ADP signaling through its receptor P2Y12, and therefore presumably Gi, regardless of the level of LSA used to activate the platelets. PKC function is required for ADP secretion and the subsequent signaling through P2Y12 regardless of the level of LSA used to activate the platelets. The end point of the LSA-induced alphaIIbbeta3-mediated signaling characterized in this study is alpha-granule secretion, which provides the fibrinogen required for aggregation of washed platelets.
authors.affiliation: Department of Microbiology and Molecular Cell Sciences, University of Memphis, Memphis, TN, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Cho
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: T I
authors.initials: TI
authors.lastname: Pestina
authors.forename: S A
authors.initials: SA
authors.lastname: Steward
authors.forename: C W
authors.initials: CW
authors.lastname: Jackson
authors.forename: T K
authors.initials: TK
authors.lastname: Gartner
mesh_terms: D000244:Adenosine Diphosphate / Q000097:blood; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology*; D015550:Cell Degranulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins / Q000097:blood; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology*; D011493:Protein Kinase C / Q000097:blood; D018048:Receptors, Purinergic P2 / Q000097:blood; D017482:Receptors, Thromboxane / Q000097:blood; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D018048:Receptors, Purinergic P2; D017482:Receptors, Thromboxane; C113734:leucyl-seryl-alanyl-arginyl-leucyl-alanyl-phenylalanine; D000244:Adenosine Diphosphate; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins