Mutations of Cys-17 and Ala-271 in the Human Histamine H₂
Receptor Determine the Species Selectivity of Guanidine-Type Agonists and Increase Constitutive Activity

URN to cite this document:

urn:nbn:de:bvb:355-epub-26717 Copy

Preuss, Hendrik ; Ghorai, Prasanta ; Kraus, Anja ; Dove, Stefan ; Buschauer, Armin ; Seifert, Roland

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Date of publication of this fulltext: 05 Aug 2009 13:40

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Details

Item type:	Article
Journal or Publication Title:	Journal of Pharmacology and Experimental Therapeutics
Publisher:	American Society for Pharmacology and Experimental Therapeutics
Volume:	321
Number of Issue or Book Chapter:	3
Page Range:	pp. 975-982
Date:	March 2007
Institutions:	Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert)
Projects:	GRK 760, Graduiertenkolleg Medizinische Chemie
Identification Number:	Value Type 10.1124/jpet.107.120519 DOI
Dewey Decimal Classification:	500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine
Status:	Published
Refereed:	Yes, this version has been refereed
Created at the University of Regensburg:	Yes
Item ID:	2671

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Abstract

In a steady-state GTPase activity assay, N-[3-(1H-imidazol-4-yl)propyl)]guanidines and N(G)-acylated derivatives are more potent and efficacious at fusion proteins of guinea pig (gpH₂R-GsαS) than human (hH₂R-GsαS) histamine H₂ receptor, coupled to the short splice variant of Gsα, GsαS. Whereas Ala-271 (hH₂R) and Asp-271 (gpH₂R) in transmembrane domain 7 were identified to determine the potency ...

Abstract

In a steady-state GTPase activity assay, N-[3-(1H-imidazol-4-yl)propyl)]guanidines and N(G)-acylated derivatives are more potent and efficacious at fusion proteins of guinea pig (gpH₂R-GsαS) than human (hH₂R-GsαS) histamine H₂ receptor, coupled to the short splice variant of Gsα, GsαS. Whereas Ala-271 (hH₂R) and Asp-271 (gpH₂R) in transmembrane domain 7 were identified to determine the potency differences of guanidine-type agonists, the molecular basis for the efficacy differences remains
to be elucidated. A homology model of the gpH₂R suggested
that an H-bond between Tyr-17 and Asp-271 stabilizes
an active receptor conformation of the gpH₂R. In the present
study, we generated a mutant hH₂R-GsαS with Cys-173Tyr-
17/Ala-2713Asp-271 exchanges (hH₂R3gpH₂R) that exhibited
an enhanced level of constitutive GTPase activity and
adenylyl cyclase activity compared with wild-type hH₂R-GsαS
and gpH₂R-GsαS. Potencies and efficacies of guanidines and
N(G)-acylguanidines were increased at this mutant receptor
compared with hH₂R-GsαS, but they were still lower than at
gpH₂R-GsαS, suggesting that aside from Tyr-17 and Asp-271
additional amino acids contribute to the distinct pharmacological profiles of both species isoforms. Another hH₂R-GsαS mutant with a Cys-173Tyr-17 exchange showed inefficient coupling to GsαS as revealed by reduced agonist-stimulated GTPase and basal adenylyl cyclase activities. Collectively, our present pharmacological study confirms the existence of an H-bond between Tyr-17 and Asp-271 favoring the stabilization of an active receptor conformation. Distinct potencies and efficacies
of agonists and inverse agonists further support the
concept of ligand-specific conformations in wild-type and mutant H₂R-GsαS fusion proteins.

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Metadata last modified: 04 Jun 2018 13:39

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