RGS domain in the amino-terminus of G protein-coupled receptor kinase 2 inhibits Gq-mediated signaling.
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.
Usui
H
H
Department of Biochemistry and Molecular Pharmacology, Chiba University Graduate, School of Medicine, Chuo-ku, Chiba 260-8670, Japan.
Nishiyama
M
M
Moroi
K
K
Shibasaki
T
T
Zhou
J
J
Ishida
J
J
Fukamizu
A
A
Haga
T
T
Sekiya
S
S
Kimura
S
S
D017607:Aluminum Compounds / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D019332:Endothelin-1 / Q000494:pharmacology; D005459:Fluorides / Q000378:metabolism; D016257:Fura-2 / Q000031:analogs & derivatives / Q000378:metabolism; D020555:GTP-Binding Protein Regulators / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000378:metabolism; D006801:Humans; D010957:Plasmids; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D051552:beta-Adrenergic Receptor Kinases
D017607:Aluminum Compounds; D019332:Endothelin-1; D020555:GTP-Binding Protein Regulators; C049925:fura-2-am; D000804:Angiotensin II; D006153:Guanosine Diphosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D019204:GTP-Binding Proteins; D005459:Fluorides; D002118:Calcium; D016257:Fura-2; C032311:aluminum fluoride