ArticleIn silico pharmacology2014
Mathematical analysis of the sodium sensitivity of the human histamine H3 receptor.
Article in In silico pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 10 citations in OpenAlex.
- Molecular Modeling of Histamine Receptors-Recent Advances in Drug Discovery.Molecules (Basel, Switzerland) · 2021Review
- Modulation of GPCRs by monovalent cations and anions.Naunyn-Schmiedeberg's archives of pharmacology · 2015Review
- Article
- Sodium binding to hH3R and hH 4R--a molecular modeling study.Journal of molecular modeling · 2014Article
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeIt 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 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.
methodsTo 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.
resultsThe 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.
conclusionThe 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.
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