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RGS Protein Regulation of CB1 Receptor‐Mediated Cannabinoid Behaviors
Author(s) -
Tai Sherrica,
Kandasamy Ram,
Barton Brenna,
Parry Logan,
Traynor John R.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.825.4
Subject(s) - heterotrimeric g protein , g protein , regulator of g protein signaling , gtpase activating protein , cannabinoid receptor , cannabinoid , rgs2 , chemistry , microbiology and biotechnology , receptor , g protein coupled receptor , protein subunit , agonist , biology , biochemistry , gene
The cannabinoid CB1 receptor, is a G protein coupled receptor and couples to members of the Gαi/o family of heterotrimeric G proteins. As such, signaling downstream of the receptor is negatively regulated by RGS proteins, or regulator of G protein signaling proteins. RGS proteins act as GAPs or GTPase accelerating proteins and bind to activated Gα‐GTP subunit to enhancing the hydrolysis of bound Gα‐GTP to Gα‐GDP, leading to inactivation of Gα subunit and the reformation of inactive G protein heterotrimer. Therefore, inhibition of RGS proteins will prolong cannabinoid signaling and possibly the potency of ligands that bind to the CB1 receptor. However, there are over 20 members of the RGS protein family and there can be redundancy among members of the family. Consequently, we developed a mouse line that expresses Gαo protein that is insensitive to the action of all RGS GAP activity. Here, F1 cross of 129SvEv/C57BL6 mice expressing a knock‐in RGS‐insensitive Gαo (RGSi‐Gαo) protein were administered the fully efficacious CB1 agonist, CP 55,940 and examined for reduction in body temperature and antinociception, two noted behaviors of CB1 agonism. CP 55,940 induced a greater reduction in body temperature in female RGSi‐Gαo mice that in their female wild‐type littermates. Latency to respond to a noxious thermal stimulus in the hot‐plate test was also greater in female RGSi‐Gαo mice compared to their female wild‐type littermates. In contrast, no differences were observed between male RGSi‐Gαo mice and their male littermates. The reasons underlying the observed sex differences are unknown. RGS proteins present a potential target for drug discovery and development that may affect the therapeutic actions of cannabinoids ligands. Support or Funding Information Supported by DA035316. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .