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Molecular Pharmacology

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Research ArticleArticle

The Effect of Mutations in the DRY Motif on the Constitutive Activity and Structural Instability of the Histamine H2Receptor

Astrid E. Alewijnse, Henk Timmerman, Edwin H. Jacobs, Martine J. Smit, Edwin Roovers, Susanna Cotecchia and Rob Leurs
Molecular Pharmacology May 2000, 57 (5) 890-898;
Astrid E. Alewijnse
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Henk Timmerman
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Edwin H. Jacobs
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Martine J. Smit
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Edwin Roovers
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Susanna Cotecchia
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Rob Leurs
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Abstract

In previous studies we showed that the wild-type histamine H2 receptor stably expressed in Chinese hamster ovary cells is constitutively active. Because constitutive activity of the H2 receptor is already found at low expression levels (300 fmol/mg protein) this receptor is a relatively unique member of the G-protein-coupled receptor (GPCR) family and a useful tool for studying GPCR activation. In this study the role of the highly conserved DRY motif in activation of the H2 receptor was investigated. Mutation of the aspartate 115 residue in this motif resulted in H2 receptors with high constitutive activity, increased agonist affinity, and increased signaling properties. In addition, the mutant receptors were shown to be highly structurally instable. Mutation of the arginine 116 residue in the DRY motif resulted also in a highly structurally instable receptor; expression of the receptor could only be detected after stabilization with either an agonist or inverse agonist. Moreover, the agonist affinity at the Arg-116 mutant receptors was increased, whereas the signal transduction properties of these receptors were decreased. We conclude that the Arg-116 mutant receptors can adopt an active conformation but have a decreased ability to couple to or activate the Gs-protein. This study examines the pivotal role of the aspartate and arginine residues of the DRY motif in GPCR function. Disruption of receptor stabilizing constraints by mutation in the DRY motif leads to the formation of active GPCR conformations, but concomitantly to GPCR instability.

Footnotes

  • Send reprint requests to: Rob Leurs, De Boelelaan 1083, 1081 HV Amsterdam, the Netherlands. E-mail: leurs{at}chem.vu.nl

  • The authors acknowledge support from the EU BIOMED2 program “Inverse Agonism: Implications for Drug Design.”

  • Abbreviations:
    GPCR
    G-protein-coupled receptor
    DMEM
    Dulbecco's modified Eagle's medium
    [125I]APT
    [125I]iodoaminopotentidine
    IBMX
    isobutylmethylxanthine
    GTPγS
    guanosine 5′-3-O-(thio)triphosphate
    • Received August 16, 1999.
    • Accepted January 25, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 57 (5)
Molecular Pharmacology
Vol. 57, Issue 5
1 May 2000
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Research ArticleArticle

The Effect of Mutations in the DRY Motif on the Constitutive Activity and Structural Instability of the Histamine H2Receptor

Astrid E. Alewijnse, Henk Timmerman, Edwin H. Jacobs, Martine J. Smit, Edwin Roovers, Susanna Cotecchia and Rob Leurs
Molecular Pharmacology May 1, 2000, 57 (5) 890-898;

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Research ArticleArticle

The Effect of Mutations in the DRY Motif on the Constitutive Activity and Structural Instability of the Histamine H2Receptor

Astrid E. Alewijnse, Henk Timmerman, Edwin H. Jacobs, Martine J. Smit, Edwin Roovers, Susanna Cotecchia and Rob Leurs
Molecular Pharmacology May 1, 2000, 57 (5) 890-898;
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