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Biochem Biophys Res Commun. 1995 Sep 5;214(1):110-7.

Lysine200 located in the fifth transmembrane domain of the histamine H1 receptor interacts with histamine but not with all H1 agonists.

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Leiden/Amsterdam Center for Drug Research, Department of Pharmacochemistry, Vrije Universiteit, The Netherlands.


Previously, we have shown that asparagine207 in the fifth transmembrane domain of the histamine H1 receptor is crucial for the binding of the N tau-nitrogen of the imidazole ring of histamine (Leurs et al., Biochem. Biophys. Res. Commun., 201, 295, 1994). In view of the potential interaction of the imidazole ring of histamine with a binding site, formed by asparagine207 and lysine200, we mutated lysine200 in the fifth transmembrane domain of the histamine H1 receptor to a non-functional alanine residue. This mutation did not affect the binding of the tested H1 receptor antagonists but resulted in a 5-fold lower affinity for histamine. The binding of other H1 receptor agonists was not affected. In stably transfected CHO cells histamine was 55-fold less effective in activating the H1Lys200Ala receptor (EC50 = 66 microM) compared to the wild type H1 receptor (EC50 = 1.2 microM). Receptor activation by the 2-methyl and the 2-(3-bromophenyl)-analogues however was hardly affected by the mutation, indicating that the 2-substituent probably prevents the interaction with the lysine200 residue. Finally, the Lys200Ala mutation reduced the production of [3H]inositol phosphates, stimulated by the non-imidazole H1 receptor agonist 2-pyridylethylamine. These data indicate that lysine200 interacts with the N pi-nitrogen of histamine and is important for the activation of the H1 receptor by histamine and the non-imidazole agonist 2-pyridylethylamine.

[Indexed for MEDLINE]

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