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Characterization of the Regulator of G Protein Signaling Domain of G Protein‐Coupled Receptor Kinase 4
Author(s) -
Keever Lindsay B,
Andresen Bradley T.
Publication year - 2006
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.20.5.a1120
Subject(s) - regulator of g protein signaling , heterotrimeric g protein , g protein coupled receptor kinase , rgs2 , g protein , gtpase activating protein , microbiology and biotechnology , g beta gamma complex , g protein coupled receptor , gtpase , chemistry , biology , signal transduction
G protein‐coupled receptor kinase 4 (GRK4) is a member of the GRK family, and is the least studied of the GRKs. Recently, two independent groups demonstrated that polymorphisms of human GRK4 are associated with essential hypertension. Two of the polymorphisms (GRK4 R65L and GRK4 A142V) lie within the regulator of G protein signaling (RGS) domain. RGS domains are found in many proteins and generally bind to GTP‐bound (active), but not GDP‐bound (inactive) Gα subunits of the heterotrimeric G proteins. This binding increases the intrinsic GTPase activity of a Gα subunit. There are RGS domains, such as the RGS domain within axin, that have not been found to interact with any Gα subunits. In the case of GRK4, no studies have been conducted on the RGS domain, but GRK4 is known to interact with Gα s ‐coupled receptors. The hypothesis being tested is that the RGS domain of GRK4 binds to active Gα s , consequently increasing the intrinsic hydrolytic rate of Gα s . Our co‐immunoprecipitation data demonstrates that His‐GRK4γ interacts with Gα s , and the interaction is increased in the presence of AlF4 ‐ . The high basal binding suggests that Gα s binds to GRK4 in the GDP‐bound state, yet the increase in binding in the presence of AlF 4 − indicates that the RGS domain preferentially binds to the GTP‐bound state. This data supports the previous findings that GRK4 inhibits D 1 dopamine receptor‐mediated signaling, and provides a potential molecular mechanism for the previously reported high basal activity of GRK4. The effect of the RGS domain on the hydrolytic rate of Gα s is currently being examined.