Serotonin 5-HT2C receptor RNA editing alters receptor basal activity: Implications for serotonergic signal transduction

Rat and human serotonin 5-HT2C receptor isoforms were evaluated for agonist -independent activation of inositol phosphate production in COS-7 cells. Th e nonedited isoform (5-HT2C-INI) displayed the greatest basal activity, sti mulating inositol phosphate production fourfold over the fully edited isofo rm (5-HT2C-VGV). All of the other isoforms tested displayed intermediate le vels of basal activity. Decreasing receptor expression levels by 50% produc ed a parallel decrease in basal activity. 5-HT stimulated inositol phosphat e production twofold over basal levels through the 5-HT2C-INI receptor and eightfold over basal levels through the 5-HT2C-VGV receptor but produced si milar maximal levels of inositol phosphate, 5-HT competition for [H-3]mesul ergine binding to 5-HT2C-INI best fit a two-site analysis with K-H = 7.6 nM and K-L = 160 nM, whereas 5-HT2C-VGV best fit a one-site model with K-i = 163 nM. [H-3]5-HT labeled 36% of the total population of 5-HT2C-INI recepto rs labeled by [H-3]mesulergine but only 12% of 5-HT2C-VGV receptors. [H-3]5 -HT K-D values increased from 5.1 nM for 5-HT2C-INI to 20 nM for 5-HT2C-VGV . [H-3]Mesulergine K-D values were the same for both isoforms, 5-HT EC50 va lues for inositol phosphate production increased from 6.1 nM for 5-HT2C-INI to 30 nM for 5-HT2C-VGV. These results demonstrate that RNA editing decrea ses 5-HT2C receptor basal activity, agonist affinity, and potency, indicati ng that RNA editing may play a role in regulating serotonergic signal trans duction and response to drug therapy.