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Keywords:

  • RNA-editing;
  • G protein coupled receptors;
  • serotonin receptors;
  • efficacy;
  • receptor-effector coupling;
  • signal transduction, agonist trafficking
  • 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