Regulation of G protein-coupled receptor kinase 5 (GRK5) by actin.

Journal Article

G protein-coupled receptor kinases (GRKs) initiate pathways leading to the desensitization of agonist-occupied G-protein-coupled receptors (GPCRs). Here we report that the cytoskeletal protein actin binds and inhibits GRK5. Actin inhibits the kinase activity directly, reducing GRK5-mediated phosphorylation of both membrane-bound GPCRs and soluble substrates. GRK5 binds actin monomers with a Kd of 0.6 microM and actin filaments with a Kd of 0. 2 microM. Mutation of 6 amino acids near the amino terminus of GRK5 eliminates actin-mediated inhibition of GRK5. Calmodulin has previously been shown to bind to the amino terminus of GRK5 (Pronin, A. N., and Benovic, J. L. (1997) J. Biol. Chem. 272, 3806-3812) and here we show calmodulin displaces GRK5 from actin. Calmodulin inhibits GRK5-mediated phosphorylation of GPCRs, but not soluble substrates such as casein. Thus in the presence of actin, calmodulin determines the substrate specificity of GRK5 by preferentially allowing phosphorylation of soluble substrates over membrane-bound substrates.

Full Text

Duke Authors

Cited Authors

  • Freeman, JL; De La Cruz, EM; Pollard, TD; Lefkowitz, RJ; Pitcher, JA

Published Date

  • August 7, 1998

Published In

Volume / Issue

  • 273 / 32

Start / End Page

  • 20653 - 20657

PubMed ID

  • 9685424

International Standard Serial Number (ISSN)

  • 0021-9258

Language

  • eng

Conference Location

  • United States