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PKC-dependent regulation of the receptor locus dominates functional consequences of cysteinyl leukotriene type 1 receptor activation

Deepak A. Deshpande^*, Rodolfo M. Pascual^*, Si-Wei Wang^*, Delrae M. Eckman^*, Ellen C. Riemer, Colin D. Funk and Raymond B. Penn^*,1

^* Department of Internal Medicine and Center for Human Genomics and

Department of Pathology, Wake Forest University Health Science, Winston-Salem, North Carolina; and

Departments of Physiology and Biochemistry, Queen’s University, Kingston, Ontario, Canada

¹Correspondence: Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA. E-mail: rpenn{at}wfubmc.edu

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 desensitization 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 LTD₄-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 CysLT1R 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.

Key Words: G protein-coupled receptor • cysteinyl leukotriene • protein kinase C • desensitization • airway smooth muscle

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				R. B. Penn and J. L. Benovic Regulation of Heterotrimeric G Protein Signaling in Airway Smooth Muscle Proceedings of the ATS, January 1, 2008; 5(1): 47 - 57. [Abstract] [Full Text] [PDF]