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Mathematical analysis of the sodium sensitivity of the human histamine H3 receptor.

ABSTRACT: PURPOSE:It was shown by several experimental studies that some G protein coupled receptors (GPCR) are sensitive to sodium ions. Furthermore, mutagenesis studies or the determination of crystal structures of the adenosine A2A or ?-opioid receptor revealed an allosteric Na(+) binding pocket near to the highly conserved Asp(2.50). Within a previous study, the influence of NaCl concentration onto the steady-state GTPase activity at the human histamine H3 receptor (hH3R) in presence of the endogenous histamine or the inverse agonist thioperamide was analyzed. The purpose of the present study was to examine and quantify the Na(+)-sensitivity of hH3R on a molecular level. METHODS:To achieve this, we developed a set of equations, describing constitutive activity and the different ligand-receptor equilibria in absence or presence of sodium ions. Furthermore, in order to gain a better understanding of the ligand- and Na(+)-binding to hH3R on molecular level, we performed molecular dynamic (MD) simulations. RESULTS:The analysis of the previously determined experimental steady-state GTPase data with the set of equations presented within this study, reveals that thioperamide binds into the orthosteric binding pocket of the hH3R in absence or presence of a Na(+) in its allosteric binding site. However, the data suggest that thioperamide binds preferentially into the hH3R in absence of a sodium ion in its allosteric site. These experimental results were supported by MD simulations of thioperamide in the binding pocket of the inactive hH3R. Furthermore, the MD simulations revealed two different binding modes for thioperamide in presence or absence of a Na(+) in its allosteric site. CONCLUSION:The mathematical model presented within this study describes the experimental data regarding the Na(+)-sensitivity of hH3R in an excellent manner. Although the present study is focused onto the Na(+)-sensitivity of the hH3R, the resulting equations, describing Na(+)- and ligand-binding to a GPCR, can be used for all other ion-sensitive GPCRs.

SUBMITTER: Wittmann HJ

PROVIDER: S-EPMC4644138 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Mathematical analysis of the sodium sensitivity of the human histamine H3 receptor.

Wittmann Hans-Joachim HJ Seifert Roland R Strasser Andrea A

In silico pharmacology 20140524 1

<h4>Purpose</h4>It was shown by several experimental studies that some G protein coupled receptors (GPCR) are sensitive to sodium ions. Furthermore, mutagenesis studies or the determination of crystal structures of the adenosine A2A or δ-opioid receptor revealed an allosteric Na(+) binding pocket near to the highly conserved Asp(2.50). Within a previous study, the influence of NaCl concentration onto the steady-state GTPase activity at the human histamine H3 receptor (hH3R) in presence of the en ...[more]

PMID: 27502620

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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.

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Mathematical analysis of the sodium sensitivity of the human histamine H3 receptor.

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Mathematical analysis of the sodium sensitivity of the human histamine H3 receptor.

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