Serotonin 5‐HT 2C Receptor RNA Editing Alters Receptor Basal Activity

: Rat and human serotonin 5‐HT 2C receptor isoforms were evaluated for agonist‐independent activation of inositol phosphate production in COS‐7 cells. The nonedited isoform (5‐HT 2C‐INI ) displayed the greatest basal activity, stimulating inositol phosphate production fourfold over the fully edited isoform (5‐HT 2C‐VGV ). All of the other isoforms tested displayed intermediate levels of basal activity. Decreasing receptor expression levels by 50% produced a parallel decrease in basal activity. 5‐HT stimulated inositol phosphate production twofold over basal levels through the 5‐HT 2C‐INI receptor and eightfold over basal levels through the 5‐HT 2C‐VGV receptor but produced similar maximal levels of inositol phosphate. 5‐HT competition for [ 3 H]mesulergine binding to 5‐HT 2C‐INI best fit a two‐site analysis with K H = 7.6 n M and K L = 160 n M , whereas 5‐HT 2C‐VGV best fit a one‐site model with K i = 163 n M . [ 3 H]5‐HT labeled 36% of the total population of 5‐HT 2C‐INI receptors labeled by [ 3 H]‐mesulergine but only 12% of 5‐HT 2C‐VGV receptors. [ 3 H]5‐HT K D values increased from 5.1 n M for 5‐HT 2C‐INI to 20 n M for 5‐HT 2C‐VGV . [ 3 H]Mesulergine K D values were the same for both isoforms. 5‐HT EC 50 values for inositol phosphate production increased from 6.1 n M for 5‐HT 2C‐INI to 30 n M for 5‐HT 2C‐VGV . These results demonstrate that RNA editing decreases 5‐HT 2C receptor basal activity, agonist affinity, and potency, indicating that RNA editing may play a role in regulating serotonergic signal transduction and response to drug therapy.