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Pharmacological Characterization of the Constitutively Activated State of the Serotonin 5‐HT 2C Receptor
Author(s) -
HERRICKDAVIS K.,
GRINDE E.,
GAUTHIER C.,
TEITLER M.
Publication year - 1998
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1998.tb10185.x
Subject(s) - receptor , class c gpcr , 5 ht receptor , inositol phosphate , agonist , inverse agonist , radioligand , 5 ht1 receptor , chemistry , endogenous agonist , g protein coupled receptor , biochemistry , serotonin , rhodopsin like receptors , radioligand assay , microbiology and biotechnology , biology , metabotropic receptor , inositol , dopamine receptor d1
Previous studies from our laboratory have shown that the 5‐HT 2C serotonin receptor can be rendered constitutively active by changing amino acid 312 (third intracellular loop) from serine to lysine (S312K). In the present study, detailed radioligand binding analyses were performed to characterize the constitutively activated state of S312K mutant receptors. All agonists tested displayed high affinity for both [ 3 H]5‐HT and [ 3 H]mesulergine binding to S312K receptors, but displayed low affinity for [ 3 H]mesulergine binding to native 5‐HT 2C receptors. [ 3 H]5‐HT labeled the same total number of S312K binding sites as [ 3 H]mesulergine. 5‐HT 2C antagonists inhibited S312K basal inositol phosphate production. These results suggest that S312K receptors mimic the active conformation of native 5‐HT 2C receptors and provide a good model system for evaluating drugs for inverse agonist activity. Also, S312K receptors may represent a new system for screening 5‐HT 2C agonist activity by comparing [ 3 H]mesulergine binding to native and S312K mutant receptors.