Dataset Information

Basal Histamine H₄ Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif.

ABSTRACT: Histamine H₄ receptor (H₄ R) orthologues are G-protein-coupled receptors (GPCRs) that exhibit species-dependent basal activity. In contrast to the basally inactive mouse H₄ R (mH₄ R), human H₄ R (hH₄ R) shows a high degree of basal activity. We have performed long-timescale molecular dynamics simulations and rigidity analyses on wild-type hH₄ R, the experimentally characterized hH₄ R variants S179M, F169V, F169V+S179M, F168A, and on mH₄ R to investigate the molecular nature of the differential basal activity. H₄ R variant-dependent differences between essential motifs of GPCR activation and structural stabilities correlate with experimentally determined basal activities and provide a molecular explanation for the differences in basal activation. Strikingly, during the MD simulations, F169^45.55 dips into the orthosteric binding pocket only in the case of hH₄ R, thus adopting the role of an agonist and contributing to the stabilization of the active state. The results shed new light on the molecular mechanism of basal H₄ R activation that are of importance for other GPCRs.

SUBMITTER: Wifling D

PROVIDER: S-EPMC7687114 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Basal Histamine H4 Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif.

Wifling David D Pfleger Christopher C Kaindl Jonas J Ibrahim Passainte P Kling Ralf C RC Buschauer Armin A Gohlke Holger H Clark Timothy T

Chemistry (Weinheim an der Bergstrasse, Germany) 20191016 64

Histamine H4 receptor (H4 R) orthologues are G-protein-coupled receptors (GPCRs) that exhibit species-dependent basal activity. In contrast to the basally inactive mouse H4 R (mH4 R), human H4 R (hH4 R) shows a high degree of basal activity. We have performed long-timescale molecular dynamics simulations and rigidity analyses on wild-type hH4 R, the experimentally characterized hH4 R variants S179M, F169V, F1 ...[more]

PMID: 31498478

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Project description:Hemorrhagic shock has a potential to be life-threatening when it is not treated. The main causes of hemorrhagic shock involve: (1) forces causing injury; and (2) diseases that can cause hemorrhage., Therefore, due to the causes of hemorrhagic shock and the life-threatening potential, the search for new methods of shock treatment is extremely valuable to the modern medicine. The aim of this study was to investigate the influence of clobenpropit in the model of hemorrhagic shock. The experiments were conducted in 110 adult male Wistar rats weighing between 205 and 470g. 1, 2 and 5 ?mol/kg of intravenous H3 receptors reverse agonists, clobentropit, and/or 1, 5 and 10 ?mol/kg H3 receptor agonist, imetit, were used as general anesthetics. Irreversible hemorrhagic shock was induced by the paused bleeding until the mean arterial pressure (MAP) lowered to the level of 20-25 mmHg. It was proved that, in cases of critical hypotension, clobenpropit triggered a dose-dependent increase of: systolic blood pressure (SBP), diastolic blood pressure (DBP), MPA and heart rate (HR) of rats with critical hypotension. The most significant changes in hemodynamic parameters were achieved by administrating dosages of 2 mmol/kg. This resulted in the survival rate increase to up to 100%. However, imetit did not trigger any hemodynamic changes nor an increase in SBP, DBP, MAP or HR. Furthermore, it was found that the premedication with prazosin, yohimbine, 6-hydroxydopamine and the vasopressin V1a receptor antagonist blocked the effects of clobenpropit. Additionally, premedication with propranolol, captopril and ZD 7155 did not cause any significant changes in the measured hemodynamic parameters. In conclusion, after an intravenous injection clobenpropit, the inverse agonist of H3 histamine receptors/agonist of histamine receptors H4, causes a resuscitating effect on rats in hemorrhagic shock. Moreover, such effect is based on the effector mechanisms of sympathetic nervous system and vasopressin.

Dataset Information

Basal Histamine H₄ Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif.

Publications

Basal Histamine H<sub>4</sub> Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif.

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