endothelin-1 and aluminum-fluoride

We have previously shown that not only G protein-coupled receptor kinase (GRK) 2, but also a catalytically inactive Lys220Trp GRK2 decreases endothelin (ET)-1-induced inositol 1,4,5-trisphosphate (IP3) formation, and demonstrated the presence of phosphorylation-independent desensitization mechanism. To clarify the role of GRK2 other than that as a kinase, we characterized an RGS (regulator of G protein signaling)-like domain in the amino-terminus of GRK2. Both GRK2(1-181) and GRK2(54-174) suppressed Ca2+ responses induced by angiotensin II (Ang II) and ET-1, and bound directly with Galphaq but not Galphas nor Galphai3 in the presence of GDP and AlF4-. These results demonstrate that GRK2 regulates Gq-mediated signaling negatively by direct interaction between its RGS domain and the transitional state of Galphaq, as well as through phosphorylation of activated receptors by its kinase domain.

Topics: Aluminum Compounds; Angiotensin II; beta-Adrenergic Receptor Kinases; Calcium; Cell Line; Cyclic AMP-Dependent Protein Kinases; Endothelin-1; Fluorides; Fura-2; GTP-Binding Protein Regulators; GTP-Binding Proteins; Guanosine Diphosphate; Humans; Plasmids; Signal Transduction; Transfection