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J. Biol. Chem., Vol. 280, Issue 10, 8722-8732, March 11, 2005

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Regulation of Cysteinyl Leukotriene Type 1 Receptor Internalization and Signaling^*

Snehal Naik, Charlotte K. Billington, Rodolfo M. Pascual¶, Deepak A. Deshpande¶, Frank P. Stefano, Trudy A. Kohout||, Delrae M. Eckman¶, Jeffrey L. Benovic, and Raymond B. Penn¶**

From the Department of Medicine, Division of Pulmonary and Critical Care Medicine, Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, Pennsylvania 19104, ^||Department of Medicine, Duke University Medical Center, Durham, North Carolina, and ^¶Department of Internal Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157

Cysteinyl leukotrienes activate the cysteinyl leukotriene type 1 receptor (CysLT1R) to regulate numerous cell functions important in inflammatory processes and diseases such as asthma. Despite its physiologic importance, no studies to date have examined the regulation of CysLT1R signaling or trafficking. We have established model systems for analyzing recombinant human CysLT1R and found regulation of internalization and signaling of the CysLT1R to be unique among G protein-coupled receptors. Rapid and profound LTD4-stimulated internalization was observed for the wild type (WT) CysLT1R, whereas a C-terminal truncation mutant exhibited impaired internalization yet signaled robustly, suggesting a region within amino acids 310–321 as critical to internalization. Although overexpression of WT arrestins significantly increased WT CysLT1R internalization, expression of dominant-negative arrestins had minimal effects, and WT CysLT1R internalized in murine embryonic fibroblasts lacking both arrestin-2 and arrestin-3, suggesting that arrestins are not the primary physiologic regulators of CysLT1Rs. Instead, pharmacologic inhibition of protein kinase C (PKC) was shown to profoundly inhibit CysLT1R internalization while greatly increasing both phosphoinositide (PI) production and calcium mobilization stimulated by LTD4 yet had almost no effect on H1 histamine receptor internalization or signaling. Moreover, mutation of putative PKC phosphorylation sites within the CysLT1R C-tail (CysLT1RS(313–316)A) reduced receptor internalization, increased PI production and calcium mobilization by LTD4, and significantly attenuated the effects of PKC inhibition. These findings characterized the CysLT1R as the first G protein-coupled receptor identified to date in which PKC is the principal regulator of both rapid agonist-dependent internalization and rapid agonist-dependent desensitization.

Received for publication, November 17, 2004

^* This study was supported by National Institutes of Health Grants AI059755, HL65338, HL67663, and GM47417. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains more detailed descriptions of CysLT1R construct generation.

^** Recipient of a Career Investigator Award from the American Lung Association. To whom correspondence should be addressed: Wake Forest University Health Sciences Center, Center for Human Genomics, Medical Center Blvd., Winston-Salem, NC 27157. Tel.: 336-713-7541; Fax: 336-713-7566; E-mail: rpenn{at}wfubmc.edu.

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