dc.contributor.author
Meyer, Johanna Charlotte
dc.date.accessioned
2020-07-30T07:39:33Z
dc.date.available
2020-07-30T07:39:33Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/27897
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-27650
dc.description.abstract
Opioid analgesics constitute the most effective treatment of severe pain, but they also
cause adverse and often fatal side effects. Selective targeting of peripheral opioid receptors
in injured tissue is a promising strategy to convey analgesia devoid of severe adverse
effects. Drug targeting to injured tissue can be achieved by exploiting the acidic pH
associated with inflammation. Yet, little is known on ligand recognition and signaling of
opioid receptors at acidic pH.
In the present study, I demonstrate that at acidic pH, μ-opioid receptor (MOR) responses
are modulated depending on a specific structural property of bound ligands. In radioligand
binding experiments, acidic pH reduced binding of naloxone (NLX) and [D-Ala2,N-Me-
Phe4,Gly5-ol]-enkephalin (DAMGO), ligands that form hydrogen bond networks to
histidine residue H297/6.52 within the receptor binding pocket. Furthermore, I observed
impaired DAMGO-induced G-protein activation (as assessed by [35S]-GTPγS binding) and
naloxone modulation of cAMP levels at acidic pH. In contrast, acidic pH did not alter G-protein
activation and cAMP responses induced by fentanyl, a ligand that is unable to form
hydrogen bonds to MOR residue H297/6.52. The exchange of residue H297/6.52 by alanine
(A) abolished high-affinity binding of [3H]-NLX and [3H]-DAMGO, as well as DAMGO-induced
G-protein activation. This mutation did not significantly alter fentanyl-induced Gprotein
activation, but reduced cAMP responses to fentanyl. I conclude that H297/6.52A is
crucial to effective binding of DAMGO and NLX to the MOR, while this residue
contributes less to the binding of fentanyl. Overall, these findings indicate that acidic pH
selectively impairs binding and consequent signaling of ligands that strongly depend on
hydrogen bond formation to H297/6.52. To ensure maximum MOR binding and signaling in
inflamed tissue, I suggest that opioid ligands should bind largely independent of H297/6.52.
en
dc.format.extent
VI, 85, iv Seiten
dc.rights.uri
http://www.fu-berlin.de/sites/refubium/rechtliches/Nutzungsbedingungen
dc.subject
µ-opioid receptor
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie::572 Biochemie
dc.title
Regulation of µ-opioid receptor function by pH
dc.contributor.gender
female
dc.contributor.firstReferee
Tauber, Rudolf
dc.contributor.furtherReferee
Daumke, Oliver
dc.date.accepted
2020-07-01
dc.identifier.urn
urn:nbn:de:kobv:188-refubium-27897-7
dc.title.translated
Regulation von Funktionen des µ-Opioidrezeptors durch den pH
de
refubium.affiliation
Biologie, Chemie, Pharmazie
dcterms.accessRights.dnb
free
dcterms.accessRights.openaire
open access