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.

scholarly journals Common Structural Basis for Constitutive Activity of the Ghrelin Receptor Family

2004 ◽  
Vol 279 (51) ◽  
pp. 53806-53817 ◽  
Author(s):  
Birgitte Holst ◽  
Nicholas D. Holliday ◽  
Anders Bach ◽  
Christian E. Elling ◽  
Helen M. Cox ◽  
...  
Keyword(s):  
Structural Basis ◽  
Constitutive Activity ◽  
Ghrelin Receptor ◽  
Receptor Family

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 Alanine-261 in intracellular loop III of the human gonadotropin-releasing hormone receptor is crucial for G-protein coupling and receptor internalization

1998 ◽  
Vol 331 (3) ◽  
pp. 893-896 ◽  
Author(s):  
David B. MYBURGH ◽  
Robert P. MILLAR ◽  
Janet P. HAPGOOD
Keyword(s):  
G Protein ◽  
Inositol Phosphate ◽  
Gnrh Receptor ◽  
Gonadotropin Releasing Hormone ◽  
Receptor Internalization ◽  
Constitutive Activity ◽  
Wild Type ◽  
Intracellular Loop ◽  
G Protein Coupling ◽  
Inositol Phosphate Production

Gonadotropin-releasing hormone (GnRH) is a decapeptide that regulates reproductive function via binding to the GnRH receptor, which is a G-protein-coupled receptor (GPCR). For several members of this family, the C-terminal domain of intracellular loop III is important in ligand-mediated coupling to G-proteins; mutations in that region can lead to constitutive activity. A specific alanine residue is involved in certain GPCRs, the equivalent of which is Ala-261 in the GnRH receptor. Mutation of this residue to Leu, Ile, Lys, Glu or Phe in the human GnRH receptor did not result in constitutive activity and instead led to complete uncoupling of the receptor (failure to support GnRH-stimulated inositol phosphate production). When this residue was mutated to Gly, Pro, Ser or Val, inositol phosphate production was still supported. All the mutants retained the ability to bind ligand, and the affinity for ligand, where measured, was unchanged. These results show that Ala-261 cannot be involved in ligand binding but is critical for coupling of the receptor to its cognate G-protein. Coupling is also dependent on the size of the residue in position 261. When the amino acid side chain has a molecular mass of less than 40 Da efficient coupling is still possible, but when its molecular mass exceeds 50 Da the receptor is uncoupled. Internalization studies on the Ala261 → Lys mutant showed a marked decrease in receptor internalization compared with the wild type, indicating that coupling is necessary for effective receptor internalization in the GnRH receptor system. Activation of protein kinase C (with PMA), but not protein kinase A (with forskolin) markedly increased the internalization of the mutant receptor while having a small effect on the wild-type receptor.

scholarly journals Regulation of meiotic prophase arrest in mouse oocytes by GPR3, a constitutive activator of the Gs G protein

2005 ◽  
Vol 171 (2) ◽  
pp. 255-265 ◽  
Author(s):  
Leon Freudzon ◽  
Rachael P. Norris ◽  
Arthur R. Hand ◽  
Shigeru Tanaka ◽  
Yoshinaga Saeki ◽  
...  
Keyword(s):  
G Protein ◽  
Meiotic Prophase ◽  
Follicle Cell ◽  
Follicle Cells ◽  
Constitutive Activity ◽  
Antral Follicles ◽  
Mouse Oocytes ◽  
Meiotic Prophase Arrest ◽  
G Protein Coupled ◽  
Receptor Family

The arrest of meiotic prophase in mouse oocytes within antral follicles requires the G protein Gs and an orphan member of the G protein–coupled receptor family, GPR3. To determine whether GPR3 activates Gs, the localization of Gαs in follicle-enclosed oocytes from Gpr3+/+ and Gpr3−/− mice was compared by using immunofluorescence and GαsGFP. GPR3 decreased the ratio of Gαs in the oocyte plasma membrane versus the cytoplasm and also decreased the amount of Gαs in the oocyte. Both of these properties indicate that GPR3 activates Gs. The follicle cells around the oocyte are also necessary to keep the oocyte in prophase, suggesting that they might activate GPR3. However, GPR3-dependent Gs activity was similar in follicle-enclosed and follicle-free oocytes. Thus, the maintenance of prophase arrest depends on the constitutive activity of GPR3 in the oocyte, and the follicle cell signal acts by a means other than increasing GPR3 activity.

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