Differential effects of regulator of G protein signaling (RGS) proteins on serotonin 5-HT1A, 5-HT2A, and dopamine D2 receptor-mediated signaling and adenylyl cyclase activity.
Regulator of G protein signaling (RGS) proteins function as GTPase accelerating proteins (GAP) for Galpha subunits, attenuating G-protein-coupled receptor signal transduction. The present study tested the ability of members of different subfamilies of RGS proteins to modulate both G-protein-dependent and -independent signaling in mammalian cells. RGS4, RGS10, and RGSZ1 significantly attenuated Galphai-mediated signaling by 5-HT1A, but not by dopamine D2, receptor-expressing cells. Additionally, RGS4 and RGS10 significantly inhibited forskolin-stimulated cAMP production in both cell lines. In contrast, RGS2, RGS7, and RGSZ1 had no effect on forskolin-stimulated cAMP production in these cells. RGS2 and RGS7 significantly decreased Galphaq-mediated signaling by 5-HT2A receptors, confirming that the RGS4 and RGS10 effects on forskolin-stimulated cAMP production were specific, and not simply due to overexpression. Interestingly, similar expression levels of RGS4 protein resulted in greater inhibition of G-protein-independent cAMP production compared to G-protein-dependent GAP activity. Our results suggest specificity and selectivity of RGS proteins on G-protein-dependent and -independent signaling in mammalian cells.
Ghavami
Afshin
A
Neuroscience Discovery Research, Wyeth Research, CN-8000, Princeton, NJ 08543-8000, USA.
Hunt
Rachel A
RA
Olsen
Michael A
MA
Zhang
Jie
J
Smith
Deborah L
DL
Kalgaonkar
Sachin
S
Rahman
Zia
Z
Young
Kathleen H
KH
D000262:Adenylyl Cyclases / Q000187:drug effects; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020710:RGS Proteins / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1 / Q000378:metabolism*; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D020710:RGS Proteins; D017448:Receptors, Dopamine D2; D044263:Receptors, Serotonin, 5-HT1; D044348:Receptors, Serotonin, 5-HT2; C098799:RGS4 protein; D005576:Colforsin; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases