title: CXCL12 regulates platelet activation via the regulator of G-protein signaling 16.
abstract: The regulators of G protein signaling (RGS) protein superfamily negatively controls G protein-coupled receptor signal transduction pathways. One of the members of this family, RGS16, is highly expressed in megakaryocytes and platelets. Studies of its function in platelet and megakaryocyte biology have been limited, in part, due to lack of pharmacological inhibitors. For example, RGS16 overexpression inhibited CXC chemokine receptor 4 (CXCR4)-mediated megakaryocyte migration. More recent studies showed that the chemokine stromal cell-derived factor (SDF1α or CXCL12) regulates platelet function via CXCR4. Based on these considerations, the present study investigated the capacity of RGS16 to regulate CXCL12-dependent platelet function, using the RGS16 knockout mouse model (Rgs16(-/-)). RGS16-deficient platelets had increased protease activated receptor 4 and collagen-induced aggregation, as well as increased CXCL12-dependent agonist-induced aggregation, dense and alpha granule secretion, integrin αIIbβ3 activation and phosphatidylserine exposure compared to those from WT littermates. CXCL12 alone did not stimulate aggregation or secretion in either RGS16-deficient or WT platelets. Furthermore, platelets from Rgs16(-/-) mice displayed enhanced phosphorylation of ERK and Akt following CXCL12 stimulation relative to controls. Finally, we also found that PKCδ is involved in regulating CXCL12-dependent activation of ERK and Akt, in the Rgs16-deficient platelets. Collectively, our findings provide the first evidence that RGS16 plays an important role in platelet function by modulating CXCL12-dependent platelet activation.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Zubair A
authors.initials: ZA
authors.lastname: Karim
authors.affiliation: Department of Pharmacology, Loma Linda University, Loma Linda, CA 92354, USA.
authors.forename: Fatima Z
authors.initials: FZ
authors.lastname: Alshbool
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Hari Priya
authors.initials: HP
authors.lastname: Vemana
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Conlon
authors.affiliation: Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID/NIH, 50 South Drive Room 4154, Bethesda, MD 20892, USA.
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Druey
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA. Electronic address: fkhasawneh@westernu.edu.
authors.forename: Fadi T
authors.initials: FT
authors.lastname: Khasawneh
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D003094:Collagen / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015151:Immunoblotting; D018345:Mice, Knockout; D010718:Phosphatidylserines / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D044462:Receptors, Proteinase-Activated / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D054377:Chemokine CXCL12; D010718:Phosphatidylserines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D020710:RGS Proteins; C107413:RGS16 protein; D044462:Receptors, Proteinase-Activated; C481942:protease-activated receptor 4, mouse; D003094:Collagen; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: CXCL12; Platelets; Regulator of G-protein signaling 16; Regulators of G-protein signaling; Signal transduction; Stromal cell-derived factor