Signaling through PI3Kgamma: a common platform for leukocyte, platelet and cardiovascular stress sensing.
The concerted activation of leukocytes and vessels shapes multiple physiological and pathological responses. A large number of these processes shares a common signal transduction platform involving the activation of plasma membrane bound G protein-coupled receptors (GPCRs). This event is usually amplified by the production of different intra-cellular second messenger molecules. Among these mediators, the phosphorylated lipid phosphatidylinositol (3,4,5)-trisphosphate (PIP3) produced by phosphoinositide 3-kinase gamma (PI3Kgamma) has recently emerged as a crucial signal in both vascular and white blood cells. The generation of mice lacking PI3Kgamma showed that the GPCR/PI3Kgamma/PIP3 signaling pathway controls diverse immune modulatory and vascular functions like respiratory burst, cell recruitment, mast cell reactivity, platelet aggregation, endothelial activation as well as smooth muscle contractility. The relative specificity of these events suggests that blocking PI3Kgamma function might turn out beneficial for diseases like inflammation, allergy, thrombosis, and major cardiovascular disorders like hypertension, thus offering a wide range of therapeutic opportunities.
Hirsch
Emilio
E
Dipartimento di Genetica, Biologia e Biochimica, University of Torino, Via Santena 5bis, 10126 Torino, Italy. emilio.hirsch@unito.it
Lembo
Giuseppe
G
Montrucchio
Giuseppe
G
Rommel
Christian
C
Costa
Carlotta
C
Barberis
Laura
L
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology*; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000201:enzymology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000517:prevention & control; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010974:Platelet Aggregation; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction
D000893:Anti-Inflammatory Agents; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse