title: Differential regulation of cysteinyl leukotriene receptor signaling by protein kinase C in human mast cells.
abstract: Cysteinyl leukotrienes (cys-LTs) are a group of lipid mediators that are potent bronchoconstrictors, powerful inducers of vascular leakage and potentiators of airway hyperresponsiveness. Cys-LTs play an essential role in asthma and are synthesized as well as activated in mast cells (MCs). Cys-LTs relay their effects mainly through two known GPCRs, CysLT1R and CysLT2R. Although protein kinase C (PKC) isoforms are implicated in the regulation of CysLT1R function, neither the role of PKCs in cys-LT-dependent MC inflammatory signaling nor the involvement of specific isoforms in MC function are known. Here, we show that PKC inhibition augmented LTD4 and LTE4-induced calcium influx through CysLT1R in MCs. In contrast, inhibition of PKCs suppressed c-fos expression as well MIP1β generation by cys-LTs. Interestingly, cys-LTs activated both PKCα and PKCε isoforms in MC. However, knockdown of PKCα augmented cys-LT mediated calcium flux, while knockdown of PKCε attenuated cys-LT induced c-fos expression and MIP1β generation. Taken together, these results demonstrate for the first time that cys-LT signaling downstream of CysLT1R in MCs is differentially regulated by two distinct PKCs which modulate inflammatory signals that have significant pathobiologic implications in allergic reactions and asthma pathology.
authors: Department of Chemistry, University of Akron, Akron, Ohio, United States of America.
authors: Vinay
authors: V
authors: Kondeti
authors: Ernest
authors: E
authors: Duah
authors: Nosayba
authors: N
authors: Al-Azzam
authors: Charles K
authors: CK
authors: Thodeti
authors: Joshua A
authors: JA
authors: Boyce
authors: Sailaja
authors: S
authors: Paruchuri
mesh_terms: D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D054407:Chemokine CCL4 / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003545:Cysteine / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D017999:Leukotriene E4 / Q000494:pharmacology; D015289:Leukotrienes / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D018077:Receptors, Leukotriene / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D054407:Chemokine CCL4; D017362:Cyclic AMP Response Element-Binding Protein; D007527:Isoenzymes; D015289:Leukotrienes; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D018077:Receptors, Leukotriene; C112381:cysteinyl-leukotriene; D017999:Leukotriene E4; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D003545:Cysteine; C083169:leukotriene D4 receptor; D002118:Calcium
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