Serotonin 5-HT2C receptor RNA editing alters receptor basal activity:: Implications for serotonergic signal transduction

被引:147
作者
Herrick-Davis, K
Grinde, E
Niswander, CM
机构
[1] Albany Med Coll, Dept Pharmacol & Neurosci, Albany, NY 12208 USA
[2] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA
关键词
RNA editing; serotonin 5-HT2C receptor; basal activity; inositol phosphate;
D O I
10.1046/j.1471-4159.1999.731711.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Rat and human serotonin 5-HT2C receptor isoforms were evaluated for agonist-independent activation of inositol phosphate production in COS-7 cells. The nonedited isoform (5-HT2C-INI) displayed the greatest basal activity, stimulating inositol phosphate production fourfold over the fully edited isoform (5-HT2C-VGV). All of the other isoforms tested displayed intermediate levels of basal activity. Decreasing receptor expression levels by 50% produced a parallel decrease in basal activity. 5-HT stimulated inositol phosphate production twofold over basal levels through the 5-HT2C-INI receptor and eightfold over basal levels through the 5-HT2C-VGV receptor but produced similar maximal levels of inositol phosphate, 5-HT competition for [H-3]mesulergine binding to 5-HT2C-INI best fit a two-site analysis with K-H = 7.6 nM and K-L = 160 nM, whereas 5-HT2C-VGV best fit a one-site model with K-i = 163 nM. [H-3]5-HT labeled 36% of the total population of 5-HT2C-INI receptors labeled by [H-3]mesulergine but only 12% of 5-HT2C-VGV receptors. [H-3]5-HT K-D values increased from 5.1 nM for 5-HT2C-INI to 20 nM for 5-HT2C-VGV. [H-3]Mesulergine K-D values were the same for both isoforms, 5-HT EC50 values for inositol phosphate production increased from 6.1 nM for 5-HT2C-INI to 30 nM for 5-HT2C-VGV. These results demonstrate that RNA editing decreases 5-HT2C receptor basal activity, agonist affinity, and potency, indicating that RNA editing may play a role in regulating serotonergic signal transduction and response to drug therapy.
引用
收藏
页码:1711 / 1717
页数:7
相关论文
共 35 条
[1]   EFFECTS OF 2ND INTRACELLULAR LOOP MUTATIONS ON SIGNAL-TRANSDUCTION AND INTERNALIZATION OF THE GONADOTROPIN-RELEASING-HORMONE RECEPTOR [J].
ARORA, KK ;
SAKAI, A ;
CATT, KJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (39) :22820-22826
[2]   Functional microdomains in g-protein-coupled receptors - The conserved Arginine-cage motif in the gonadotropin-releasing hormone receptor [J].
Ballesteros, J ;
Kitanovic, S ;
Guarnieri, F ;
Davies, P ;
Fromme, BJ ;
Konvicka, K ;
Chi, L ;
Millar, RP ;
Davidson, JS ;
Weinstein, H ;
Sealfon, SC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (17) :10445-10453
[3]  
BARKER EL, 1994, J BIOL CHEM, V269, P11687
[4]   Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: Evidence for agonist-directed trafficking of receptor stimulus [J].
Berg, KA ;
Maayani, S ;
Goldfarb, J ;
Scaramellini, C ;
Leff, P ;
Clarke, WP .
MOLECULAR PHARMACOLOGY, 1998, 54 (01) :94-104
[5]  
Berg KA, 1996, MOL PHARMACOL, V50, P1017
[6]  
BERGLUND J, 1994, TERR ABSTR, V2, P2
[7]   Regulation of serotonin-2C receptor G-protein coupling by RNA editing [J].
Burns, CM ;
Chu, H ;
Rueter, SM ;
Hutchinson, LK ;
Canton, H ;
SandersBush, E ;
Emeson, RB .
NATURE, 1997, 387 (6630) :303-308
[8]   APOLIPOPROTEIN B-48 IS THE PRODUCT OF A MESSENGER-RNA WITH AN ORGAN-SPECIFIC IN-FRAME STOP CODON [J].
CHEN, SH ;
HABIB, G ;
YANG, CY ;
GU, ZW ;
LEE, BR ;
WENG, SA ;
SILBERMAN, SR ;
CAI, SJ ;
DESLYPERE, JP ;
ROSSENEU, M ;
GOTTO, AM ;
LI, WH ;
CHAN, L .
SCIENCE, 1987, 238 (4825) :363-366
[9]   REGIONS OF THE ALPHA-1-ADRENERGIC RECEPTOR INVOLVED IN COUPLING TO PHOSPHATIDYLINOSITOL HYDROLYSIS AND ENHANCED SENSITIVITY OF BIOLOGICAL FUNCTION [J].
COTECCHIA, S ;
EXUM, S ;
CARON, MG ;
LEFKOWITZ, RJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (08) :2896-2900
[10]  
Egan CT, 1998, J PHARMACOL EXP THER, V286, P85