Mutations of Cys-17 and Ala-271 in the Human Histamine H<sub>2</sub>Receptor Determine the Species Selectivity of Guanidine-Type Agonists and Increase Constitutive Activity

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

doi:10.1124/jpet.107.120519

Cited by 16 publications

(22 citation statements)

References 29 publications

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“…The control data for hH 2 R-G S␣S and gpH 2 R-G S␣S are identical with the control data for these constructs in Fig. 4 of Preuss et al (2007).…”

Section: Analysis Of H 2 R Species Isoforms 991supporting

confidence: 63%

“…K B values and inverse agonist efficacies, respectively, of antagonists at hH 2 R-G s␣S were compared with the corresponding parameters at gpH 2 R-G s␣S , rH 2 R-G s␣S , and cH 2 R-G s␣S , respectively, using one-way ANOVA. The control data for hH 2 R-G S␣S and gpH 2 R-G S␣S are identical with the control data for these constructs in Table 2 of Preuss et al (2007 G s␣S (ϳ29% reduction) and gpH 2 R plus G s␣S (ϳ23% reduction). Taken together, among H 2 R species isoforms coexpressed with G s␣S , cH 2 R was the most constitutively active GPCR.…”

Section: Regulation Of Ac Activities In Membranes Expressing Fused Ansupporting

confidence: 58%

“…GTP Effect), the effect of GTP (10 M) was referred to the effect of GTP (10 M) plus HA (100 M). The control data for hH 2 R-G S␣S and gpH 2 R-G S␣S are identical with the control data for these constructs in Table 3 of Preuss et al (2007 C terminus on the constitutive activities of various GPCRs was described previously (Prezeau et al, 1996;WenzelSeifert and Seifert, 2003). Ligand-Specific Interactions at H 2 R Species Isoforms.…”

Section: Analysis Of H 2 R Species Isoforms 991supporting

confidence: 54%

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Constitutive Activity and Ligand Selectivity of Human, Guinea Pig, Rat, and Canine Histamine H₂Receptors

Preuss

Ghorai²,

Kraus³

et al. 2007

J Pharmacol Exp Ther

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Previous studies revealed pharmacological differences between human and guinea pig histamine H 2 receptors (H 2 Rs) with respect to the interaction with guanidine-type agonists. Because H 2 R species variants are structurally very similar, comparative studies are suited to relate different properties of H 2 R species isoforms to few molecular determinants. Therefore, we systematically compared H 2 Rs of human (h), guinea pig (gp), rat (r), and canine (c). Fusion proteins of hH 2 R, gpH 2 R, rH 2 R, and cH 2 R, respectively, and the short splice variant of G s␣ , G s␣S , were expressed in Sf9 insect cells. In the membrane steady-state GTPase activity assay, cH 2 R-G s␣S but neither gpH 2 R-G s␣S nor rH 2 R-G s␣S showed the hallmarks of increased constitutive activity compared with hH 2 R-G s␣S , i.e., increased efficacies of partial agonists, increased potencies of agonists with the extent of potency increase being correlated with the corresponding efficacies at hH 2 R-G s␣S , increased inverse agonist efficacies, and decreased potencies of antagonists. Furthermore, in membranes expressing nonfused H 2 Rs without or together with mammalian G s␣S or H 2 R-G s␣ fusion proteins, the highest basal and GTP-dependent increases in adenylyl cyclase activity were observed for cH 2 R. An example of ligand selectivity is given by metiamide, acting as an inverse agonist at hH 2 R-G s␣S , gpH 2 R-G s␣S , and rH 2 R-G s␣S in the GTPase assay in contrast to being a weak partial agonist with decreased potency at cH 2 R-G s␣S . In conclusion, the cH 2 R exhibits increased constitutive activity compared with hH 2 R, gpH 2 R, and rH 2 R, and there is evidence for ligand-specific conformations in H 2 R species isoforms.The histamine H 2 receptor (H 2 R) species isoforms of canine (Gantz et al., 1991b), human (Gantz et al., 1991a), rat (Ruat et al., 1991), and guinea pig (Traiffort et al., 1995) were cloned. The four H 2 R species isoforms are closely related to each other, as is reflected by an overall amino acid sequence identity of more than 80%. The highest conservation exists within the seven ␣-helical transmembrane (TM) domains (sequence identity of more than 90%), whereas the N-terminal domain together with the extracellular end of TM1 and the C terminus are the least conserved regions (Fig. 1).Despite this high degree of structural similarity, N-[3-(1H-imidazol-4-yl)propyl]guanidines such as compounds 8 to 10 (Fig. 2) differentially activate guinea pig (gpH 2 R) and human (hH 2 R) H 2 receptors. In a membrane steady-state GTPase activity assay using fusion proteins of H 2 R and the short splice variant of G s␣ , G s␣S , such H 2 R-selective agonists are considerably more potent and efficacious at gpH 2 R-G s␣S than at hH 2 R-G s␣S (Kelley et al., 2001). By contrast, the small H 2 R agonists histamine (1, HA), dimaprit (2, DIM), amthamine (3, AMT), and betahistine (4, BET) are unselective between these species. Recently, a novel class of N G -acylated imida- Article, publication date, and citation information can be fo...

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“…The control data for hH 2 R-G S␣S and gpH 2 R-G S␣S are identical with the control data for these constructs in Fig. 4 of Preuss et al (2007).…”

Section: Analysis Of H 2 R Species Isoforms 991supporting

confidence: 63%

Section: Regulation Of Ac Activities In Membranes Expressing Fused Ansupporting

confidence: 58%

Section: Analysis Of H 2 R Species Isoforms 991supporting

confidence: 54%

See 1 more Smart Citation

Constitutive Activity and Ligand Selectivity of Human, Guinea Pig, Rat, and Canine Histamine H₂Receptors

Preuss

Ghorai²,

Kraus³

et al. 2007

J Pharmacol Exp Ther

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“…This technique allows us to obtain useful information about the interactions of amino acids with the ligand in the binding pocket. Beyond the H 1 R, the analysis of receptor species isoforms has also been most valuable for the H 2 R (Preuss et al, 2007a), H 3 R (Ligneau et al, 2000), and H 4 R (Thurmond et al, 2004).…”

mentioning

confidence: 99%

Molecular Basis for the Selective Interaction of Synthetic Agonists with the Human Histamine H₁-Receptor Compared with the Guinea Pig H₁-Receptor

Straßer

Wittmann²,

Kunze³

et al. 2008

Mol Pharmacol

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Previous studies revealed that phenylhistamines and histaprodifens possess higher potency and affinity at guinea pig histamine H 1 -receptor (gpH 1 R) than at human histamine H 1 -receptor (hH 1 R). However, we recently identified an imidazolylpropyl-with higher potency and efficacy at hH 1 R compared with gpH 1 R. The aim of this study was to reveal the molecular basis for the species differences of synthetic ligands. We studied 11 novel phenylhistamines and phenoprodifens. H 1 R species isoforms were expressed in Sf9 insect cells, and [3 H]mepyramine competition binding and GTPase assays were performed. We identified bulky phenylhistamines with higher potency and affinity at hH 1 R compared with gpH 1 R. Molecular dynamics simulations of ligand-H 1 R interactions revealed four potential binding modes for phenylhistamines possessing an additional histamine moiety; the terminal histamine moiety showed a high flexibility in the binding pocket. There are striking similarities in ligand properties in bulky phenylhistamines and UR-AK57. Comparison of bulky phenylhistamine binding mode with binding mode of UR-AK57 suggests that only one of these four binding modes should be established. The higher potency is explained by more effective van der Waals interaction of the compounds with Asn 2.61 (hH 1 R) relative to Ser 2.61 (gpH 1 R). In addition, two stable binding modes for phenoprodifens with different orientations in the binding-pocket were identified. Depending on phenoprodifen orientation, the highly conserved Trp 6.48 , part of the toggle switch involved in receptor activation, was found in an inactive or active conformation, respectively. We identified the first phenylhistamines with higher potency at hH 1 R than at gpH 1 R and obtained insight into the binding mode of bulky phenylhistamines and imidazolylpropylguanidines.

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“…The H 4 -receptor possesses very high constitutive activity as well. Similar constitutive activity renders the system well suited for the analysis of species-specific ligand effects, since differences in constitutive activity between GPCRs can alter their pharmacological profiles and lead to a further complication of data interpretation [40,41].…”

Section: R Expressed In Sk-n-mc Cells By [ 3 H]namhmentioning

confidence: 99%

Comparison of the pharmacological properties of human and rat histamine H3-receptors

Schnell

Straßer

Seifert

2010

Biochemical Pharmacology

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Mutations of Cys-17 and Ala-271 in the Human Histamine H₂Receptor Determine the Species Selectivity of Guanidine-Type Agonists and Increase Constitutive Activity

Cited by 16 publications

References 29 publications

Constitutive Activity and Ligand Selectivity of Human, Guinea Pig, Rat, and Canine Histamine H₂Receptors

Constitutive Activity and Ligand Selectivity of Human, Guinea Pig, Rat, and Canine Histamine H₂Receptors

Molecular Basis for the Selective Interaction of Synthetic Agonists with the Human Histamine H₁-Receptor Compared with the Guinea Pig H₁-Receptor

Comparison of the pharmacological properties of human and rat histamine H3-receptors

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Mutations of Cys-17 and Ala-271 in the Human Histamine H2Receptor Determine the Species Selectivity of Guanidine-Type Agonists and Increase Constitutive Activity

Cited by 16 publications

References 29 publications

Constitutive Activity and Ligand Selectivity of Human, Guinea Pig, Rat, and Canine Histamine H2Receptors

Constitutive Activity and Ligand Selectivity of Human, Guinea Pig, Rat, and Canine Histamine H2Receptors

Molecular Basis for the Selective Interaction of Synthetic Agonists with the Human Histamine H1-Receptor Compared with the Guinea Pig H1-Receptor

Comparison of the pharmacological properties of human and rat histamine H3-receptors

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Mutations of Cys-17 and Ala-271 in the Human Histamine H₂Receptor Determine the Species Selectivity of Guanidine-Type Agonists and Increase Constitutive Activity

Constitutive Activity and Ligand Selectivity of Human, Guinea Pig, Rat, and Canine Histamine H₂Receptors

Constitutive Activity and Ligand Selectivity of Human, Guinea Pig, Rat, and Canine Histamine H₂Receptors

Molecular Basis for the Selective Interaction of Synthetic Agonists with the Human Histamine H₁-Receptor Compared with the Guinea Pig H₁-Receptor