RNA‐editing of the 5‐HT_2C receptor alters agonist‐receptor‐effector coupling specificity

Abstract

1 The serotonin 2C (5-HT 2C ) receptor couples to both phospholipase C (PLC)-inositol phosphate (IP) and phospholipase A 2 (PLA 2 )-arachidonic acid (AA) signalling cascades. Agonists can dierentially activate these eectors (i.e. agonist-directed tracking of receptor stimulus) perhaps due to agonist-speci®c receptor conformations which dierentially couple to/activate transducer molecules (e.g. G proteins). Since editing of RNA transcripts of the human 5-HT 2C 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 PLA 2 -AA pathways in CHO cells stably expressing two major, fully RNA-edited isoforms (5-HT 2C-VSV , 5-HT 2C-VGV ) of the h5-HT 2C receptor. 2 5-HT increased AA release and IP accumulation in both 5-HT 2C-VSV and 5-HT 2C-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-HT 2C-INI ) when receptors were expressed at similar levels. 3 Consistent with our previous report, the ecacy 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 tracking of receptor stimulus. However, with the RNA-edited receptor isoforms there was no dierence in the relative ecacies of TFMPP or bufotenin for AA release and IP accumulation suggesting that the capacity for 5-HT 2C agonists to trac receptor stimulus is lost as a result of RNA editing. 4 These results suggest an important role for the second intracellular loop in transmitting agonistspeci®c information to signalling molecules.

Central Serotonin2C Receptor: From Physiology to Pathology

“…Interestingly, it was shown that coupling of 5-HT 2C receptors to G 13 and G q/11 can be differentially stimulated by certain agonists; ergots preferentially G q/11 , whereas 5-HT and (S)-2-(chloro-5-flouro-indo-l-yl)-l-methylethylamine fumarate (RO 60-0175), a selective 5-HT 2C receptor agonist, are equally efficacious towards both pathways. Differential Gprotein coupling appeared to depend on receptor reserve [95] and was regulated by RNA editing [80,96]. The latter may alter the ability of LSD to stimulate IP3 formation.…”

Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide

“…For example, the edited isoform VSV (Val156-Ser158-Val160) has 4-fold reduced constitutive activity and 4-to 5-fold reduced potency to initiate intracellular signals relative to the unedited isoform INI. 18,[24][25][26][27][28][29][30] Thus, increased editing of the 5HT 2C R could lead to reduced responsiveness to serotonin and could represent one of the vulnerability factors that predispose some individuals to suicide.…”

Reduced levels of protein recoding by A-to-I RNA editing in Alzheimer's disease

“…However, naturally, much interest has been focused on the minute fraction of editing sites in protein coding genes that result in amino acid substitutions, also known as the recoding sites (Sommer et al 1991;Niswender et al 1999;Berg et al 2001;Hoopengardner et al 2003;Iwamoto and Kato 2003;Bhalla et al 2004;Cenci et al 2008;Schellekens et al 2012). Recoding by A-to-I editing is a highly regulated process, whereas deregulated recoding has been associated with multiple ailments (Paz et al 2007;Slotkin and Nishikura 2013;Tomaselli et al 2014;Paz-Yaacov et al 2015).…”