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Ligand‐directed signaling of the serotonin 2A receptor depends on βarrestin‐2
Author(s) -
Bohn Laura M,
Raehal Kirsten M.,
Schmid Cullen L.
Publication year - 2008
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.22.1_supplement.725.11
Subject(s) - serotonergic , serotonin , arrestin , neurotransmitter , receptor , microbiology and biotechnology , internalization , 5 ht receptor , chemistry , neuroscience , pharmacology , medicine , signal transduction , biology , endocrinology , g protein coupled receptor , biochemistry
The serotonin 2A receptor (5‐HT2AR) mediates the effects of hallucinogenic drugs such as DOI and LSD, as well as the neurotransmitter serotonin. Using mouse embryonic fibroblasts (MEFs) that lack βarrestins and mice that lack βarr2 (βarr2), we show that there is difference in signaling and trafficking of the 5‐HT2AR that diverges at point of βarrestin interactions. In MEFs, DOI induces internalization and activates ERK1/2 in a βarrestin‐independent manner, while serotonin requires βarrestins to internalize the receptor and to mediate most of the ERK1/2 activation. In WT frontal cortical neurons, the 5‐HT2AR is intracellularly distributed; however in βarr2‐KO neurons, the receptor is expressed on the cell surface. WT mice display a head twitch response when treated with hallucinogenic serotonergic agonists and the same response can be observed following high doses of the serotonin precursor, 5‐hydroxytryptophan (5‐HTP). βArr2‐KO mice display head twitches in response to DOI but not to 5‐HTP. Both 5‐HTP and DOI treatments induce ERK1/2 activation in WT frontal cortex; however, only DOI activates ERK in βarr2‐KO mice. Our findings demonstrate that 5‐HT2AR activation by two distinct agonists diverges at the point of βarrestin interactions; in the absence of βarr2, differences between the behavioral responses to these drugs are revealed. NIDA funding: K01 DA14460 (LMB); F31 DA219532 (KMR).