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Vol. 57, Issue 4, 826-831, April 2000
q
Department of Molecular Pharmacology and Pathology, Consorzio Mario
Negri Sud, Istituto di Ricerche Farmacologiche, "Mario Negri",
Santa Maria Imbaro (M.S., S.M., E.D., L.I., A.D.B.), and Istituto
Neurologico Mediterraneo Neuromed, Pozzilli, Italy (M.S., A.D.B.)
In this study, we investigated the regulation of different G
protein-coupled receptor (GPCR)-stimulated signaling pathways by GPCR
kinase 2 (GRK2). We used thyrotropin receptor, which is coupled to
different G proteins, to investigate the regulation of G
s- and
Gq-mediated signaling (assessed by cAMP and inositol phosphate
production, respectively). In transfected cells, both pathways were
desensitized by GRK2. However a kinase-dead GRK2 mutant (GRK2-K220R)
only decreased inositol phosphate production, indicating that GRK2
could regulate Gq signaling through a phosphorylation-independent mechanism. Similar results were obtained with serotonin receptor 5-hydroxytryptamine2C, which is coupled to Gq. This
effect was mimicked by the N-terminal domain of GRK2 (GRK2-Nter), but
not by the C-terminal domain. In cells transfected with Gq, direct activation of Gq signaling (by AlF4
) was
desensitized by GRK2-Nter, indicating an effect at the G-level. For
comparison, in parallel samples we studied a protein regulator of G
protein signaling RGS4 and we found a similar regulatory profile. We
therefore hypothesized that the GRK2-Nter could directly interact with
the Gq subunit to regulate its signaling, as demonstrated for
several RGS proteins. This hypothesis is further supported by the
presence, within the GRK2-Nter, of an RGS homology domain. In direct
binding experiments, we found that GRK2-Nter interacts with Gq (only
when activated) but not with Gs and Go. We conclude that GRK2,
besides desensitizing the GPCR by phosphorylation, is able to
selectively bind to Gq and to regulate its signaling.
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