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In‐Vivo Functional Properties of the Fully Edited 5‐HT2C Receptor
Author(s) -
Olaghere da Silva Uade Brimmy,
SandersBush Elaine
Publication year - 2009
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.23.1_supplement.942.3
Subject(s) - agonist , gene isoform , in vivo , receptor , antagonist , partial agonist , in vitro , genetically modified mouse , pharmacology , chemistry , transgene , biology , microbiology and biotechnology , biochemistry , genetics , gene
In‐Vitro studies of RNA editing of the serotonin type 2C receptor (5‐HT 2C R) have shown a pronounced loss of function in the fully edited isoform (VGV). Our goal is to evaluate functional coupling of the edited 5‐HT 2C R in‐vivo using transgenic mice that solely express the VGV isoform. In order to accomplish this goal, we established selective activation of the receptor both in‐vitro and in‐vivo. Since pharmacological studies are not available for mice, we compared the relative affinity of antagonists for 5‐HT 2A versus 5‐HT 2C receptors, confirming that M100907 and SB206553 were relatively selective. Nearly a decade ago, our laboratory showed that RNA editing of the 5‐HT 2C R to generate the VGV isoform silences constitutive activity of the receptor, eliminates high affinity agonist binding, and decreases agonist potency in cell culture. We now demonstrate, in‐vivo, a decrease in GTP‐sensitive high affinity binding from 5% in wild‐type mice to less than 0.1% in transgenic mice solely expressing the VGV isoform. We have also observed a marked 20‐fold increase in5‐HT 2C R receptor density, as well as, an increased agonist and antagonist sensitivity in locomotor activity. (Supported by NIH grants T32MH065782 and R01MH34007)