DC Element | Wert | Sprache |
dc.contributor.author | Shalaeva, Dacia N. | |
dc.contributor.author | Cherepanov, Dmitry A. | |
dc.contributor.author | Galperin, Michael Y. | |
dc.contributor.author | Vriend, Geri | |
dc.contributor.author | Mulkidjanian, Armen Y. | |
dc.date.accessioned | 2021-12-23T16:22:10Z | - |
dc.date.available | 2021-12-23T16:22:10Z | - |
dc.date.issued | 2019 | |
dc.identifier.issn | 00052736 | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/14190 | - |
dc.description.abstract | The human genome contains about 700 genes of G protein-coupled receptors (GPCRs) of class A; these seven-helical membrane proteins are the targets of almost half of all known drugs. In the middle of the helix bundle, crystal structures reveal a highly conserved sodium-binding site, which is connected with the extracellular side by a water-filled tunnel. This binding site contains a sodium ion in those GPCRs that are crystallized in their inactive conformations but does not in those GPCRs that are trapped in agonist-bound active conformations. The escape route of the sodium ion upon the inactive-to-active transition and its very direction have until now remained obscure. Here, by modeling the available experimental data, we show that the sodium gradient over the cell membrane increases the sensitivity of GPCRs if their activation is thermodynamically coupled to the sodium ion translocation into the cytoplasm but decreases it if the sodium ion retreats into the extracellular space upon receptor activation. The model quantitatively describes the available data on both activation and suppression of distinct GPCRs by membrane voltage. The model also predicts selective amplification of the signal from (endogenous) agonists if only they, but not their (partial) analogs, induce sodium translocation. Comparative structure and sequence analyses of sodium-binding GPCRs indicate a key role for the conserved leucine residue in the second transmembrane helix (Leu2.46) in coupling sodium translocation to receptor activation. Hence, class A GPCRs appear to harness the energy of the transmembrane sodium potential to increase their sensitivity and selectivity. | |
dc.description.sponsorship | Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG); EvoCell Program of the Osnabrueck University; Ostpartnerschaftenprogramm of the German Academic Exchange Service; Russian Science FoundationRussian Science Foundation (RSF) [14-50-00029]; Russian Government [AAAA-A19-119012890064-7]; Intramural Research Program of the NIH at the National Library of Medicine; Federal Ministry of Education and Research of GermanyFederal Ministry of Education & Research (BMBF); The authors would like to thank Profs. V. Katritch, H.-J. Steinhoff and H. Vogel for encouragement and very useful discussions. Helpful advices from Drs. N.P. Isaev and J. Klare are greatly appreciated. The calculations were done using the equipment of the shared research facilities of HPC computing resources at Lomonosov Moscow State University supported by its Development Program. This study was supported by the Deutsche Forschungsgemeinschaft, Federal Ministry of Education and Research of Germany, the EvoCell Program of the Osnabrueck University (AYM), the Ostpartnerschaftenprogramm of the German Academic Exchange Service, the 14-50-00029 grant from the Russian Science Foundation (DNS), and the Russian Government contract AAAA-A19-119012890064-7 (DAC). MYG is supported by the Intramural Research Program of the NIH at the National Library of Medicine. | |
dc.language.iso | en | |
dc.publisher | ELSEVIER | |
dc.relation.ispartof | BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES | |
dc.subject | 2-STATE MODEL | |
dc.subject | Adrenoreceptor | |
dc.subject | Agonist binding | |
dc.subject | ALLOSTERIC MODULATION | |
dc.subject | ATP SYNTHASES | |
dc.subject | BINDING-SITE | |
dc.subject | Biochemistry & Molecular Biology | |
dc.subject | Biophysics | |
dc.subject | Cell signaling | |
dc.subject | CRYSTAL-STRUCTURE | |
dc.subject | DOPAMINE D-2S RECEPTOR | |
dc.subject | GPCR | |
dc.subject | HELIX F | |
dc.subject | Membrane potential | |
dc.subject | Muscarinic receptor | |
dc.subject | Receptor activation | |
dc.subject | SODIUM | |
dc.subject | Sodium transport | |
dc.subject | STRUCTURAL INSIGHTS | |
dc.subject | VOLTAGE-SENSITIVITY | |
dc.title | G protein-coupled receptors of class A harness the energy of membrane potential to increase their sensitivity and selectivity | |
dc.type | journal article | |
dc.identifier.doi | 10.1016/j.bbamem.2019.183051 | |
dc.identifier.isi | ISI:000493222200002 | |
dc.description.volume | 1861 | |
dc.description.issue | 12 | |
dc.contributor.orcid | 0000-0002-2265-5572 | |
dc.contributor.orcid | 0000-0001-6286-4638 | |
dc.contributor.researcherid | AAH-3608-2021 | |
dc.contributor.researcherid | B-5859-2013 | |
dc.contributor.researcherid | R-8391-2016 | |
dc.identifier.eissn | 18792642 | |
dc.publisher.place | RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS | |
dcterms.isPartOf.abbreviation | Biochim. Biophys. Acta-Biomembr. | |
dcterms.oaStatus | Green Accepted, Bronze | |