Back to Search
Start Over
Lipid-mediated Regulation of G Protein-coupled Receptor Kinases 2 and 3
- Source :
- Journal of Biological Chemistry. 270:5742-5747
- Publication Year :
- 1995
- Publisher :
- Elsevier BV, 1995.
-
Abstract
- G protein-coupled receptor-mediated signaling is attenuated by a process referred to as desensitization, wherein agonist-dependent phosphorylation of receptors by G protein-coupled receptor kinases (GRKs) is proposed to be a key initial event. However, mechanisms that activate GRKs are not fully understood. In one scenario, beta gamma-subunits of G proteins (G beta gamma) activate certain GRKs (beta-adrenergic receptor kinases 1 and 2, or GRK2 and GRK3), via a pleckstrin homology domain in the COOH terminus. This interaction has been proposed to translocate cytosolic beta-adrenergic receptor kinases (beta ARKs) to the plasma membrane and facilitate interaction with receptor substrates. Here, we report a novel finding that membrane lipids modulate beta ARK activity in vitro in a manner that is analogous and competitive with G beta gamma. Several lipids, including phosphatidylserine (PS), stimulated, whereas phosphatidylinositol 4,5-bisphosphate inhibited, the ability of these GRKs to phosphorylate agonist-occupied m2 muscarinic acetylcholine receptors. Furthermore, both PS and phosphatidylinositol 4,5-bisphosphate specifically bound to beta ARK1, whereas phosphatidylcholine, a lipid that did not modulate beta ARK activity, did not bind to beta ARK1. The lipid regulation of beta ARKs did not occur via a modulation of its autophosphorylation state. PS- and G beta gamma-mediated stimulation of beta ARK1 was compared and found strikingly similar; moreover, their effects together were not additive (except at initial stages of reaction), which suggests that PS and G beta gamma employed a common interaction and activation mechanism with the kinase. The effects of these lipids were prevented by two well known G beta gamma-binding proteins, phosducin and GST-beta ARK-(466-689) fusion protein, suggesting that the G beta gamma-binding domain (possibly the pleckstrin homology domain) of the GRKs is also a site for lipid:protein interaction. We submit the intriguing possibility that both lipids and G proteins co-regulate the function of GRKs.
- Subjects :
- G-Protein-Coupled Receptor Kinase 3
Macromolecular Substances
G protein
Recombinant Fusion Proteins
Membrane lipids
Protein Serine-Threonine Kinases
Spodoptera
Biology
Transfection
Binding, Competitive
Biochemistry
chemistry.chemical_compound
GTP-Binding Proteins
Animals
Humans
Phosphatidylinositol
Molecular Biology
Phospholipids
Glutathione Transferase
G protein-coupled receptor
G protein-coupled receptor kinase
Kinase
Cell Membrane
Autophosphorylation
Receptor Protein-Tyrosine Kinases
Cell Biology
Cyclic AMP-Dependent Protein Kinases
Receptors, Muscarinic
Cell biology
Enzyme Activation
Pleckstrin homology domain
Kinetics
chemistry
beta-Adrenergic Receptor Kinases
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 270
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....eb19d83ea1a4b69e0ca8a9b2e09a3cff