JPET Introducing ALZET?ew Model 2006 Pump

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on December 7, 2007; DOI: 10.1124/jpet.107.131524

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.107.131524v1
324/3/1084    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Berg, K. A.
Right arrow Articles by Clarke, W. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Berg, K. A.
Right arrow Articles by Clarke, W. P.


Received for publication September 12, 2007.
Revised December 5, 2007.
Accepted for publication December 6, 2007.

A Conservative, Single Amino Acid Substitution in the Second Cytoplasmic Domain of the h5-HT2C Receptor Alters Both Ligand-dependent and Ligand-independent Receptor Signaling

Kelly A. Berg 1*, John Dunlop 2, Teresa Sanchez 1, Michelle Silva 1, William P. Clarke 1

1 University of Texas Health Science Center 2 Wyeth Research

* Address correspondence to: E-mail: berg{at}uthscsa.edu

Abstract

The post-transcriptional process of mRNA editing changes up to three amino acids in the second intracellular (i2) domain of the serotonin2C (5-HT2C) receptor and alters some signaling characteristics of the receptor. Here we report that the substitution of valine for isoleucine (I156V; 5- HT2C-VNI), which occurs naturally as a result of mRNA editing, alters both ligand-dependent and -independent signaling. Agonist functional selectivity at the 5-HT2C-VNI receptor differed from the non-edited 5-HT2C-INI receptor. Ligands with selectivity for phospholipase C (PLC) signaling in 5-HT2C-INI cells, retained this selectivity in 5-HT2C-VNI expressing cells. However, ligands with selectivity for phospholipase A2 (PLA2) signaling in 5-HT2C-INI cells, lost the capacity for preferential PLA2 activation in 5-HT2C-VNI cells. Maximal PLC responses elicited by 5-HT (full agonist) and LSD and DOI (partial agonists) at edited receptors (5-HT2C-VNI, 5-HT2C-VSV and 5-HT2C-VGV) were not different from 5-HT2C-INI receptors, suggesting that the capacity of the agonist-occupied receptor to couple to Gq/11 proteins was not different. Ligand-independent (i.e. constitutive) receptor activity toward PLC for the 5-HT2C-VNI receptor was markedly reduced, to a level similar to that for the fully edited 5-HT2C-VSV isoform. However, there was no difference in the thermal stability of the edited receptors, suggesting that mRNA editing does not alter the capacity of receptors to adopt active conformations. These results indicate that a conservative change in one amino acid (I156V) located in i2 of the 5-HT2C receptor produces profound changes in receptor function that differ depending upon whether the receptor is unoccupied, or occupied by agonist.


Key words: GPCR, RNA editing, phospholipase A2, phospholipase C, serotonin receptor, signal transduction




Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2007 by the American Society for Pharmacology and Experimental Therapeutics.