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The interaction of G protein‐coupled receptor kinase 4γ with Gα s is required for inhibition of the β 2 ‐AR
Author(s) -
Andresen Bradley T.,
Flynn Megan K.,
Sisk Kay,
Bastepe Murat,
Jackson Edwin K.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.585.3
Subject(s) - receptor , g protein coupled receptor , gnas complex locus , beta adrenergic receptor kinase , g protein coupled receptor kinase , desensitization (medicine) , g protein , signal transduction , microbiology and biotechnology , homologous desensitization , phosphorylation , chemistry , adrenergic receptor , biology , biochemistry , gene
Polymorphisms in G protein receptor kinase 4γ (GRK4γ) have been implicated in hypertension via desensitizing Gs‐coupled receptors, such as the β 2 ‐adrenergic receptor (β 2 ‐AR). However, the molecular mechanism initiating phosphorylation and desensitization is unknown. Previous data demonstrate that GRK4γ interacts with inactive Gα s ; thus, we hypothesized that the interaction of GRK4γ with Gα s is required for proper desensitization of the β 2 ‐AR. To test this, we identified Gα s constructs that do not fully interact with GRK4γ and used these constructs in functional studies utilizing Gnas E2‐/E2‐ mouse embryonic fibroblasts (MEFs), which are functionally Gα s knockouts. The data suggest that GRK4γ binds to Gα s ; however, the precise area and amino acids involved in binding has yet to be identified. Moreover, the data confirm that expression of Gα s in Gnas E2‐/E2‐ MEFs restores isoproterenol‐mediated generation of cAMP, which is inhibited by GRK4γ; however, when GRK4γ does not bind to Gα s it cannot inhibit β 2 ‐ARs. In conclusion, the data suggests that GRK4γ binds to inactive Gα s positioning it near the receptor, and upon activation of the receptor Gα s dissociates from the receptor, Gβγ, and GRK4γ, resulting in signaling; then GRK4γ, which has previously been reported to be constitutively active, has access to the receptor and phosphorylates and desensitizes the receptor. This work was supported by the AHAF and is supported by a VISN 15 grant.