Determining the role of RGS proteins in opioid biochemistry and behavior
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Authors
Smith, Chelsea E.
Issue Date
2011
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
Opioids are potent analgesic drugs prescribed to treat pain that ranges from moderate to
severe. They have unwanted side effects, can lead to tolerance and dependence, and display
addictive properties. Opioids function by acting on mu opioid receptors (MORs) located
throughout the CNS. MOR is coupled to inhibitory heterotrimeric G proteins of the Gαi/o
family, which have many downstream signaling effects, including inhibition of adenylyl
cyclase. Regulators of G protein signaling (RGS) proteins negatively modulate this
receptor-mediated G protein signaling. One of the remaining questions regarding the effects
of RGS proteins on MOR signaling is which, if any, Gαi/o protein subtype serves as the site
of action for RGS protein inhibition of opioid signaling. To evaluate the role of one Gα
subunit, Gαo, in the effects of RGS proteins on opioid signaling, MOR-mediated
biochemistry was evaluated in mice that express an RGS- insensitive (RGSi), mutant Gαo
protein (Gαo -RGSi). In particular, MOR expression and function was measured using
saturation radioligand binding with agonist [3H]DAMGO and MOR agonist-stimulated
[35S]GTPγS binding, respectively, while G protein expression was evaluated by Western
blot. Mice possessing the knock-in mutation showed no changes in total MOR expression,
but showed decreased agonist-stimulated G protein activation. This loss in stimulation
could be attributed to a decrease in the expression of Gαo, Gαz, Gβ1-4 and Gγ2 proteins in
the Gαo-RGSi +/GS mice. These changes in G protein expression and activity are likely a
result of compensation in response to the increased signaling produced by the RGSi
mutation. Thus, it will be difficult to use these mice as a model for studying RGS proteins
due to these compensatory changes in the opioid signaling system. Nevertheless, this,shows
that RGS proteins play an essential role in the basic control of MOR signaling.
Description
iv, 27 p.
Citation
Publisher
Kalamazoo College
License
U.S. copyright laws protect this material. Commercial use or distribution of this material is not permitted without prior written permission of the copyright holder.