scholarly journals The Target Residence Time of Antihistamines Determines Their Antagonism of the G Protein-Coupled Histamine H1 Receptor

2017 ◽  
Vol 8 ◽  
Author(s):  
Reggie Bosma ◽  
Gesa Witt ◽  
Lea A. I. Vaas ◽  
Ivana Josimovic ◽  
Philip Gribbon ◽  
...  
Keyword(s):  
G Protein ◽  
Residence Time ◽  
H1 Receptor ◽  
Histamine H1 Receptor ◽  
G Protein Coupled

scholarly journals Structure of the human histamine H1 receptor gene

1998 ◽  
Vol 335 (3) ◽  
pp. 663-670 ◽  
Author(s):  
Marianne D. DE BACKER ◽  
Inge LOONEN ◽  
Peter VERHASSELT ◽  
Jean-Marc NEEFS ◽  
Walter H. M.L. LUYTEN
Keyword(s):  
G Protein ◽  
Untranslated Region ◽  
Receptor Gene ◽  
Promoter Sequence ◽  
Start Codon ◽  
Luciferase Reporter ◽  
H1 Receptor ◽  
Histamine H1 Receptor ◽  
G Protein Coupled ◽  
Human Histamine

Histamine H1 receptor expression has been reported to change in disorders such as allergic rhinitis, autoimmune myocarditis, rheumatoid arthritis and atherosclerosis. Here we report the isolation and characterization of genomic clones containing the 5´ flanking (regulatory) region of the human histamine H1 receptor gene. An intron of approx. 5.8 kb was identified in the 5´ untranslated region, which suggests that an entire subfamily of G-protein-coupled receptors may contain an intron immediately upstream of the start codon. The transcription initiation site was mapped by 5´ rapid amplification of cDNA ends to a region 6.2 kb upstream of the start codon. Immediately upstream of the transcription start site a fragment of 1.85 kb was identified that showed promoter activity when placed upstream of a luciferase reporter gene and transiently transfected into cells expressing the histamine H1 receptor. The promoter sequence shares a number of characteristics with the promoter sequences of other G-protein-coupled receptor encoding genes, including binding sites for several transcription factors, and the absence of TATA and CAAT sequences at the appropriate locations. The promoter sequence described here differs from that reported previously [Fukui, Fujimoto, Mizuguchi, Sakamoto, Horio, Takai, Yamada and Ito (1994) Biochem. Biophys. Res. Commun. 201, 894–901] because the reported genomic clone was chimaeric. Furthermore our study provides evidence that the 3´ untranslated region of the H1 receptor mRNA is much longer than previously accepted. Together, these findings provide a complete view of the structure of the human histamine H1 receptor gene. Both the coding region of the H1 receptor gene and its promoter region were independently mapped to chromosome 3p25.

scholarly journals Route to Prolonged Residence Time at the Histamine H1 Receptor: Growing from Desloratadine to Rupatadine

2019 ◽  
Vol 62 (14) ◽  
pp. 6630-6644 ◽  
Author(s):  
Reggie Bosma ◽  
Zhiyong Wang ◽  
Albert J. Kooistra ◽  
Nick Bushby ◽  
Sebastiaan Kuhne ◽  
...  
Keyword(s):  
Residence Time ◽  
H1 Receptor ◽  
Histamine H1 Receptor

Drug-Target Residence Time-A Case for G Protein-Coupled Receptors

2014 ◽  
Vol 34 (4) ◽  
pp. 856-892 ◽  
Author(s):  
Dong Guo ◽  
Julia M. Hillger ◽  
Adriaan P. IJzerman ◽  
Laura H. Heitman
Keyword(s):  
G Protein ◽  
Residence Time ◽  
Drug Target ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

scholarly journals Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E4106.30×30K Variant in the Histamine H1 Receptor

2021 ◽  
Vol 22 (7) ◽  
pp. 3702
Author(s):  
Xiaoyuan Ma ◽  
Marta Arimont Segura ◽  
Barbara Zarzycka ◽  
Henry F. Vischer ◽  
Rob Leurs
Keyword(s):  
G Protein ◽  
Missense Variant ◽  
Histamine Receptor ◽  
Structural Basis ◽  
Constitutive Activity ◽  
Wild Type ◽  
H1 Receptor ◽  
Histamine H1 Receptor ◽  
Missense Variants ◽  
Receptor Family

The Exome Aggregation Consortium has collected the protein-encoding DNA sequences of almost 61,000 unrelated humans. Analysis of this dataset for G protein-coupled receptor (GPCR) proteins (available at GPCRdb) revealed a total of 463 naturally occurring genetic missense variations in the histamine receptor family. In this research, we have analyzed the distribution of these missense variations in the four histamine receptor subtypes concerning structural segments and sites important for GPCR function. Four missense variants R1273.52×52H, R13934.57×57H, R4096.29×29H, and E4106.30×30 K, were selected for the histamine H1 receptor (H1R) that were hypothesized to affect receptor activity by interfering with the interaction pattern of the highly conserved D(E)RY motif, the so-called ionic lock. The E4106.30×30 K missense variant displays higher constitutive activity in G protein signaling as compared to wild-type H1R, whereas the opposite was observed for R1273.52×52H, R13934.57×57H, and R4096.29×29H. The E4106.30×30 K missense variant displays a higher affinity for the endogenous agonist histamine than wild-type H1R, whereas antagonist affinity was not affected. These data support the hypothesis that the E4106.30×30 K mutation shifts the equilibrium towards active conformations. The study of these selected missense variants gives additional insight into the structural basis of H1R activation and, moreover, highlights that missense variants can result in pharmacologically different behavior as compared to wild-type receptors and should consequently be considered in the drug discovery process.

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