Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphoinositide (PI) 3-kinases are critical regulators of mast cell degranulation. The Class IA PI 3-kinases p85/p110beta and p85/p110delta but not p85/p110alpha are required for antigen-mediated calcium flux in RBL-2H3 cells (Smith, A. J., Surviladze, Z., Gaudet, E. A., Backer, J. M., Mitchell, C. A., and Wilson, B. S. et al., (2001) J. Biol. Chem. 276, 17213-17220). We now examine the role of Class IA PI 3-kinases isoforms in degranulation itself, using a single-cell degranulation assay that measures the binding of fluorescently tagged annexin V to phosphatidylserine in the outer leaflet of the plasma membrane of degranulated mast cells. Consistent with previous data, antibodies against p110delta and p110beta blocked FcepsilonR1-mediated degranulation in response to FcepsilonRI ligation. However, antigen-stimulated degranulation was also inhibited by antibodies against p110alpha, despite the fact that these antibodies have no effect on antigen-induced calcium flux. These data suggest that p110alpha mediates a calcium-independent signal during degranulation. In contrast, only p110beta was required for enhancement of antigen-stimulated degranulation by adenosine, which augments mast cell-mediated airway inflammation in asthma. Finally, we examined carbachol-stimulated degranulation in RBL2H3 cells stably expressing the M1 muscarinic receptor (RBL-2H3-M1 cells). Surprisingly, carbachol-stimulated degranulation was blocked by antibody-mediated inhibition of the Class III PI 3-kinase hVPS34 or by titration of its product with FYVE domains. Antibodies against Class IA PI 3-kinases had no effect. These data demonstrate: (a) a calcium-independent role for p110alpha in antigen-stimulated degranulation; (b) a requirement for p110beta in adenosine receptor signaling; and (c) a requirement for hVPS34 during M1 muscarinic receptor signaling. Elucidation of the intersections between these distinct pathways will lead to new insights into mast cell degranulation.
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PMID:Distinct phosphoinositide 3-kinases mediate mast cell degranulation in response to G-protein-coupled versus FcepsilonRI receptors. 1252 21

Calcium antagonists (CAs) or calcium-channel blockers are a common group of antihypertensive medications. These drugs have the property of blocking the calcium channels of vascular and cardiac smooth muscle fibers. Some of these drugs may inhibit the growth and proliferation of vascular smooth muscle cells and fibroblasts, and inhibit the synthesis of extracellular-matrix proteins (collagen, fibronectin, proteoglycans). Other CAs also have immunomodulatory or dysregulatory effects on lymphocytes and can suppress superoxide generation and phagocytic action of neutrophils. Moreover mast cell degranulation and platelet aggregation may also be impaired. On account of these properties, calcium antagonists have also been used for the prevention and treatment of various dermatologic diseases such as erythromelalgia, idiopathic- or CREST-related calcinosis cutis, primary and secondary Raynaud phenomenon, chilblains, chronic anal fissures, keloids, and burn scars. They are also used for prevention of skin flap necrosis in experimental models. Calcium antagonists, apart from their well known and established antihypertensive action, should also be considered as possible therapy for several dermatologic diseases.
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PMID:Calcium antagonists in dermatology: a review of the evidence and research-based studies. 1615 Feb 16