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Identifier

000349945

Title

Μηχανισμοί ρύθμισης της αναλγητικής δράσης των οπιοειδών από την RGS9-2

Author

Ψηφογεώργου, Κάσση

Thesis advisor

Ζαχαρίου, Βενετία

Reviewer

Καρδάσης, Δημήτρης
Πλαίτάκης, Ανδρέας

Abstract

Regulators of G protein signaling (RGS) proteins, modulate G protein coupled receptor responsiveness through their GTPase activity. RGS exert signaling termination by binding to activated Gα subunit of G proteins via their RGS domain. We are particularly interested in RGS9-2 a multifunctional protein and a member of RGS family which is highly concentrated in striatum but also localized in regions that mediate addiction and analgesia. We have previously shown that RGS9-/- (KO) mice show enhanced morphine analgesia and delayed development of tolerance (Zachariou et al.,2003). In our effort to comprehend the mechanism via which RGS9-2 modulates opioid actions we investigated the role of RGS9-2 in mu opioid receptor functional responses. According to our data, in PC12 and MEF cells RGS9-2 delays morphine or DAMGO-mediated MOR endocytosis. To exert this action, RGS9-2 is located to the cell membrane through the binding of its DEP domain to transmembrane proteins. The overexpression of RGS9-2 in PC12 cells leads to inhibition of ERK phosphorylation in an agonist dependent manner, a system that is affected by MOR activation. In striatum the levels of RGS9 are exclusively regulated by morphine and its expression leads to inhibition of ERK stimulation which is enhanced when RGS9 is not expressed (RGS9-2-/- tissues). The participation of RGS9 in the signaling complexes that are formed after acute or chronic stimulation of MOR by opioids, gives an additive role to RGS9. Depending on the agonist stimulation and protein interactions with Gβ5 and Gα subunits, as well as β-arrestin2, RGS9 can act as a positive or as a negative regulator of the analgesic effect.

Language

Greek

Subject

Analgesics, Opioid

GTP-Binding Proteins

Issue date

2008-12-15

Collection

School/Department--School of Medicine--Department of Medicine--Doctoral theses

Type of Work--Doctoral theses

Permanent Link

https://elocus.lib.uoc.gr//dlib/d/6/0/metadata-dlib-6d2aee5c775280de0e201d07c84e5e32_1253765346.tkl