dc.contributor.author
Meyer, Johanna
dc.contributor.author
Del Vecchio, Giovanna
dc.contributor.author
Seitz, Viola
dc.contributor.author
Massaly, Nicolas
dc.contributor.author
Stein, Christoph
dc.date.accessioned
2022-01-06T12:16:40Z
dc.date.available
2022-01-06T12:16:40Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/33358
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-33079
dc.description.abstract
Background and Purpose: Adverse side effects of conventional opioids can be avoided if ligands selectively activate peripheral opioid receptors in injured tissue. Injury and inflammation are typically accompanied by acidification. In this study, we examined influences of low pH and mutation of the ionizable amino acid residue H297(6.52) on mu-opioid receptor binding and signalling induced by the mu-opioid receptor ligands fentanyl, DAMGO, and naloxone.
Experimental Approach: HEK 293 cells stably transfected with mu-opioid receptors were used to study opioid ligand binding, [S-35]-GTP gamma S binding, and cAMP reduction at physiological and acidic pH. We used mu-opioid receptors mutated at H297(6.52) to A (MOR-H297(6.52)A) to delineate ligand-specific interactions with H297(6.52).
Key Results: Low pH and the mutant receptor MOR-H297(6.52)A impaired naloxone binding and antagonism of cAMP reduction. In addition, DAMGO binding and G-protein activation were decreased under these conditions. Fentanyl-induced signalling was not influenced by pH and largely independent of H297(6.52).
Conclusions and Implications: Our investigations indicate that low pH selectively impairs mu-opioid receptor signalling modulated by ligands capable of forming hydrogen bonds with H297(6.52). We propose that protonation of H297(6.52) at acidic pH reduces binding and subsequent signalling of such ligands. Novel agonists targeting opioid receptors in injured tissue might benefit from lack of hydrogen bond formation with H297(6.52).
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
HEK293 cells
en
dc.subject
μ-opioid receptor
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Modulation of μ‐opioid receptor activation by acidic pH is dependent on ligand structure and an ionizable amino acid residue
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.doi
10.1111/bph.14810
dcterms.bibliographicCitation.journaltitle
British Journal of Pharmacology
dcterms.bibliographicCitation.number
23
dcterms.bibliographicCitation.originalpublishername
Wiley
dcterms.bibliographicCitation.pagestart
4510
dcterms.bibliographicCitation.pageend
4520
dcterms.bibliographicCitation.volume
176
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.funding
DEAL Wiley
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
31355457
dcterms.isPartOf.issn
0007-1188
dcterms.isPartOf.eissn
1476-5381