PT  - JOURNAL ARTICLE
AU  - Christina M. Godin
AU  - Lucimar T. Ferreira
AU  - Lianne B. Dale
AU  - Robert Gros
AU  - Sean P. Cregan
AU  - Stephen S. G. Ferguson
TI  - The Small GTPase Ral Couples the Angiotensin II Type 1 Receptor to the Activation of Phospholipase C-δ1
AID  - 10.1124/mol.109.061069
DP  - 2010 Mar 01
TA  - Molecular Pharmacology
PG  - 388--395
VI  - 77
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/77/3/388.short
4100  - http://molpharm.aspetjournals.org/content/77/3/388.full
SO  - Mol Pharmacol2010 Mar 01; 77
AB  - The angiotensin II type 1 receptor (AT1R) plays an important role in cardiovascular function and as such represents a primary target for therapeutic intervention. The AT1R has traditionally been considered to be coupled to the activation of phospholipase C (PLC) β via its association with Gαq/11, leading to increases in intracellular inositol phosphate (IP) and release of calcium from intracellular stores. In the present study, we investigated whether the small GTPase RalA contributed to the regulation of AT1R endocytosis and signaling. We find that neither RalA nor RalB is required for the endocytosis of the AT1R, but that RalA expression is required for AT1R-stimulated IP formation but not 5-HT2A receptor-mediated IP formation. AT1R-activated IP formation is lost in the absence of Ral guanine nucleotide dissociation stimulator (RalGDS), and requires the β-arrestin-dependent plasma membrane translocation of RalGDS. Gαq/11 small interfering RNA (siRNA) treatment also significantly attenuates both AT1R- and 5-HT2A receptor-stimulated IP formation after 30 min of agonist stimulation. PLC-δ1 has been reported to be activated by RalA, and we show that AT1R-stimulated IP formation is attenuated after PLC-δ1 siRNA treatment. Taken together, our results provide evidence for a G protein-coupled recepto-activated and RalGDS/Ral-mediated mechanism for PLC-δ1 stimulation.Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics