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

Kelly A. Berg, Jodie D. Cropper, Colleen M. Niswender, Elaine Sanders-Bush, Ronald B. Emeson, William P. Clarke

Research output: Contribution to journalArticlepeer-review

115 Scopus citations

Abstract

1. 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. 2. 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. 3. 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. 4. These results suggest an important role for the second intracellular loop in transmitting agonist-specific information to signalling molecules.

Original languageEnglish (US)
Pages (from-to)386-392
Number of pages7
JournalBritish Journal of Pharmacology
Volume134
Issue number2
DOIs
StatePublished - 2001

Keywords

  • Agonist trafficking
  • Eceptor-effector coupling
  • Efficacy
  • G protein coupled receptors
  • RNA-editing
  • Serotonin receptors
  • Signal transduction

ASJC Scopus subject areas

  • Pharmacology

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