Linked Life Data

12821660

Source:http://linkedlifedata.com/resource/pubmed/id/12821660

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
37
pubmed:dateCreated
2003-9-8
pubmed:abstractText
Agonist-induced phosphorylation of beta-adrenergic receptors (beta ARs) by G protein-coupled receptor kinases (GRKs) results in their desensitization followed by internalization. Whether protein kinase A (PKA)-mediated phosphorylation of beta ARs, particularly the beta 1AR subtype, can also trigger internalization is currently not known. To test this, we cloned the mouse wild type beta 1AR (WT beta 1AR) and created 3 mutants lacking, respectively: the putative PKA phosphorylation sites (PKA-beta 1AR), the putative GRK phosphorylation sites (GRK-beta 1AR), and both sets of phosphorylation sites (PKA-/GRK-beta 1AR). Following agonist stimulation, both PKA-beta 1AR and GRK-beta 1AR mutants showed comparable increases in phosphorylation and desensitization. Saturating concentrations of agonist induced only 50% internalization of either mutant compared with wild type, suggesting that both PKA and GRK phosphorylation of the receptor contributed to receptor sequestration in an additive manner. Moreover, in contrast to the WT beta 1AR and PKA-beta 1AR, sequestration of the GRK-beta 1AR and PKA-/GRK-beta 1AR was independent of beta-arrestin recruitment. Importantly, clathrin inhibitors abolished agonist-dependent internalization for both the WT beta 1AR and PKA-beta 1AR, whereas caveolae inhibitors prevented internalization only of the GRK-beta 1AR mutant. Taken together, these data demonstrate that: 1) PKA-mediated phosphorylation can trigger agonist-induced internalization of the beta 1AR and 2) the pathway selected for beta 1AR internalization is primarily determined by the kinase that phosphorylates the receptor, i.e. PKA-mediated phosphorylation directs internalization via a caveolae pathway, whereas GRK-mediated phosphorylation directs it through clathrin-coated pits.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
12
pubmed:volume
278
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
35403-11
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:12821660-Animals, pubmed-meshheading:12821660-Binding Sites, pubmed-meshheading:12821660-Cell Line, pubmed-meshheading:12821660-Cloning, Molecular, pubmed-meshheading:12821660-Cyclic AMP-Dependent Protein Kinases, pubmed-meshheading:12821660-Dobutamine, pubmed-meshheading:12821660-Endocytosis, pubmed-meshheading:12821660-GTP-Binding Proteins, pubmed-meshheading:12821660-Humans, pubmed-meshheading:12821660-Mice, pubmed-meshheading:12821660-Models, Molecular, pubmed-meshheading:12821660-Phosphorylation, pubmed-meshheading:12821660-Protein Structure, Secondary, pubmed-meshheading:12821660-Receptor Protein-Tyrosine Kinases, pubmed-meshheading:12821660-Receptors, Adrenergic, beta-1, pubmed-meshheading:12821660-Receptors, Adrenergic, beta-2, pubmed-meshheading:12821660-Recombinant Proteins, pubmed-meshheading:12821660-Sequence Deletion, pubmed-meshheading:12821660-Transfection
pubmed:year
2003
pubmed:articleTitle
Protein kinase A and G protein-coupled receptor kinase phosphorylation mediates beta-1 adrenergic receptor endocytosis through different pathways.
pubmed:affiliation
Department of Medicine and Cell Biology, Medical Center, Duke University, Durham, North Carolina 27710, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't