RNA‐editing of the 5‐HT2C receptor alters agonist‐receptor‐effector coupling specificity

Open Access
Publisher Website
Google Scholar
Abstract
The serotonin2C (5‐HT2C) receptor couples to both phospholipase C (PLC)‐inositol phosphate (IP) and phospholipase A2 (PLA2)‐arachidonic acid (AA) signalling cascades. Agonists can differentially activate these effectors (i.e. agonist‐directed trafficking of receptor stimulus) perhaps due to agonist‐specific receptor conformations which differentially couple to/activate transducer molecules (e.g. G proteins). Since editing of RNA transcripts of the human 5‐HT2C receptor leads to substitution of amino acids at positions 156, 158 and 160 of the putative second intracellular loop, a region important for G protein coupling, we examined the capacity of agonists to activate both the PLC‐IP and PLA2‐AA pathways in CHO cells stably expressing two major, fully RNA‐edited isoforms (5‐HT2C‐VSV, 5‐HT2C‐VGV) of the h5‐HT2C receptor. 5‐HT increased AA release and IP accumulation in both 5‐HT2C‐VSV and 5‐HT2C‐VGV expressing cells. As expected, the potency of 5‐HT for both RNA‐edited isoforms for both responses was 10 fold lower relative to that of the non‐edited receptor (5‐HT2C‐INI) when receptors were expressed at similar levels. Consistent with our previous report, the efficacy order of two 5‐HT receptor agonists (TFMPP and bufotenin) was reversed for AA release and IP accumulation at the non‐edited receptor thus demonstrating agonist trafficking of receptor stimulus. However, with the RNA‐edited receptor isoforms there was no difference in the relative efficacies of TFMPP or bufotenin for AA release and IP accumulation suggesting that the capacity for 5‐HT2C agonists to traffic receptor stimulus is lost as a result of RNA editing. These results suggest an important role for the second intracellular loop in transmitting agonist‐specific information to signalling molecules. British Journal of Pharmacology (2001) 134, 386–392; doi:10.1038/sj.bjp.0704255