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PKC‐dependent regulation of the receptor locus dominates functional consequences of cysteinyl leukotriene type 1 receptor activation
Author(s) -
Deshpande Deepak A.,
Pascual Rodolfo M.,
Wang Si-Wei,
Eckman Delrae M.,
Riemer Ellen C.,
Funk Colin D.,
Penn Raymond B.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-8060com
Subject(s) - protein kinase c , bronchoconstriction , microbiology and biotechnology , desensitization (medicine) , receptor , leukotriene , leukotriene d4 , lipid signaling , chemotaxis , chemistry , g protein coupled receptor , calcium in biology , signal transduction , biology , intracellular , immunology , antagonist , asthma , biochemistry
Leukotrienes are important lipid mediators of asthma that contribute to airway inflammation and bronchoconstriction. Critical mechanisms for physiological regulation of the main G protein‐coupled receptor (GPCR) mediating the leukotriene responses in asthma, cysteinyl leukotriene type 1 receptor (CysLT1R), have not been delineated. Although desen‐sitization of GPCRs is a well‐established phenomenon, studies demonstrating its physiological relevance are lacking. Here, we demonstrate that relief of PKC‐mediated desensitization of endogenous CysLT1Rs augments multiple LTD 4 ‐stimulated cellular functions, with associated increases in intracellular signaling events. In analyses of airway smooth muscle contraction ex vivo , PKC inhibition augmented LTD4‐stimulated contraction, and increased phosphoinositide hydrolysis and calcium flux in both murine and human airway smooth muscle cells. Similarly, for human monocytes, PKC inhibition augmented LTD4‐stimulated calcium flux and cell migration assessed in transwell chamber experiments and also augmented LTD4‐induced production of monocyte chemotactic protein assessed by ELISA. In contrast, PKC inhibition had no effect or slightly attenuated these cell functions and signaling events promoted by other receptor agonists, suggesting that despite antithetical effects on downstream events, desensitization of the CysLT1R is the principal mechanism by which PKC regulates the functional consequences of CysLTIR activation.—Deshpande, D. A., Pascual, R. M., Wang, S.‐W., Eckman, D. M., Riemer, E. C., Funk, C. D., Penn, R. B. PKC‐dependent regulation of the receptor locus dominates functional consequences of cysteinyl leukotriene type 1 receptor activation. FASEB J. 21, 2335–2342 (2007)