Lipid-mediated regulation of G protein-coupled receptor kinases 2 and 3

S. K. DebBurman, J. Ptasienski, E. Boetticher, J. W. Lomasney, J. L. Benovic, M. M. Hosey*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

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, Bγ-subunits of G proteins (Gβγ) activate certain GRKs (β-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 β-adrenergic receptor kinases (βARKs) to the plasma membrane and facilitate interaction with receptor substrates. Here, we report a novel finding that membrane lipids modulate βARK activity in vitro in a manner that is analogous and competitive with G(βγ). 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 βARK1, whereas phosphatidylcholine, a lipid that did not modulate BARK activity, did not bind to βARK1. The lipid regulation of βARKs did not occur via a modulation of its autophosphorylation state. PS- and G(βγ)- mediated stimulation of βARK1 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(βγ) employed a common interaction and activation mechanism with the kinase. The effects of these lipids were prevented by two well known G(βγ)binding proteins, phosducin and GST-βARK-(466-689) fusion protein, suggesting that the G(βγ)-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.

Original languageEnglish (US)
Pages (from-to)5742-5747
Number of pages6
JournalJournal of Biological Chemistry
Volume270
Issue number11
DOIs
StatePublished - 1995

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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