PT  - JOURNAL ARTICLE
AU  - Christina M Godin
AU  - Lucimar T Ferreira
AU  - Lianne B Dale
AU  - Robert Gros
AU  - Sean P Cregan
AU  - Stephen SG Ferguson
TI  - THE SMALL GTPASE RAL COUPLES THE ANGIOTENSIN II TYPE 1 RECEPTOR TO THE ACTIVATION OF PHOSPHOLIPASEC-δ1
AID  - 10.1124/mol.109.061069
DP  - 2009 Dec 16
TA  - Molecular Pharmacology
PG  - mol.109.061069
4099  - http://molpharm.aspetjournals.org/content/early/2009/12/16/mol.109.061069.short
4100  - http://molpharm.aspetjournals.org/content/early/2009/12/16/mol.109.061069.full
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 Cβ 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 are 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 siRNA treatment also significantly attenuates both AT1R-5-HT2A receptor stimulated IP formation following 30 minutes of agonist stimulation. PLC-δ1 has been reported to be activated by RalA and we show here that AT1R-stimulated IP formation is attenuated following PLC-δ1 siRNA treatment. Taken together, our results provide evidence for a GPCR activated and RalGDS/Ral-mediated mechanism for PLC-δ1 stimulation.The American Society for Pharmacology and Experimental Therapeutics