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Molecular Pharmacology

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Research ArticleArticle

A Dileucine-Based Motif in the C-Terminal Tail of the Lutropin/Choriogonadotropin Receptor Inhibits Endocytosis of the Agonist-Receptor Complex

Kazuto Nakamura and Mario Ascoli
Molecular Pharmacology October 1999, 56 (4) 728-736;
Kazuto Nakamura
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Mario Ascoli
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Abstract

The rat lutropin/choriogonadotropin receptor (rLHR) is a member of the rhodopsin-like subfamily of G protein-coupled receptors that has two adjacent dileucine motifs in the C-terminal cytoplasmic tail. Here we show that simultaneous (L613,614,615,616A) or individual (L613,L614A or L615,616A) mutation of the two adjacent dileucine motifs to alanines results in mutants with enhanced rates of agonist-induced internalization. The L613,L614A mutation was much more effective in enhancing internalization than the L615,L616A mutation. Moreover, the L613A mutation was more effective than the L614A mutation. Because in the human LHR the residues equivalent to L613 and L614 of the rLHR are a phenylalanine and a leucine (F635 and L636), we also prepared mutants that exchanged these motifs. In the rLHR, an LL-to-FL exchange enhanced endocytosis, and in the human LHR, an FL-to-LL exchange impaired endocytosis. The internalization of rLHR-wt and rLRH-L613,L614A was inhibited by coexpression of the clathrin-binding domain of β-arrestin. In fact, this manipulation reduced the enhanced rate of internalization of rLHR-L613,614A back to that of rLHR-wt. The L613,614A mutation does not affect the degradation of the internalized agonist or the membrane targeting of the nascent rLHR. The L615,616A mutation also did not affect degradation of the internalized agonist but impaired the membrane targeting of the nascent rLHR. We conclude that the dileucine-based motifs of the rLHR inhibit internalization and suggest that this inhibition may be due to an impairment in the binding of the rLHR to endogenous nonvisual arrestins.

Footnotes

  • Send reprint requests to: Dr. Mario Ascoli, Department of Pharmacology, 2-319A BSB, The University of Iowa, Iowa City, IA 52242-1109. E-mail: mario-ascoli{at}uiowa.edu

  • This work was supported by National Institutes of Health Grant CA40629 (to M.A.). The services and facilities provided by the Diabetes and Endocrinology Research Center of the University of Iowa (supported by National Institutes of Health Grant DK25295) are also gratefully acknowledged. K.N. was partially supported by a fellowship from the Lalor Foundation.

  • Abbreviations:
    GPCR
    G protein-coupled receptor
    AP
    adaptor protein
    wt
    wild type
    ke
    endocytotic rate constant
    CG
    choriogonadotropin
    LHR
    lutropin/choriogonadotropin receptor
    rLHR
    rat lutropin/choriogonadotropin receptor
    hLHR
    human lutropin/choriogonadotropin receptor
    • Received March 11, 1999.
    • Accepted June 15, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (4)
Molecular Pharmacology
Vol. 56, Issue 4
1 Oct 1999
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Research ArticleArticle

A Dileucine-Based Motif in the C-Terminal Tail of the Lutropin/Choriogonadotropin Receptor Inhibits Endocytosis of the Agonist-Receptor Complex

Kazuto Nakamura and Mario Ascoli
Molecular Pharmacology October 1, 1999, 56 (4) 728-736;

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Research ArticleArticle

A Dileucine-Based Motif in the C-Terminal Tail of the Lutropin/Choriogonadotropin Receptor Inhibits Endocytosis of the Agonist-Receptor Complex

Kazuto Nakamura and Mario Ascoli
Molecular Pharmacology October 1, 1999, 56 (4) 728-736;
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