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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
34
pubmed:dateCreated
2000-9-25
pubmed:abstractText
G protein-coupled receptor kinases (GRKs) specifically recognize and phosphorylate the agonist-occupied form of numerous G protein-coupled receptors (GPCRs), ultimately resulting in desensitization of receptor signaling. Until recently, GPCRs were considered to be the only natural substrates for GRKs. However, the recent discovery that GRKs also phosphorylate tubulin raised the possibility that additional GRK substrates exist and that the cellular role of GRKs may be much broader than just GPCR regulation. Here we report that synucleins are a novel class of GRK substrates. Synucleins (alpha, beta, gamma, and synoretin) are 14-kDa proteins that are highly expressed in brain but also found in numerous other tissues. alpha-Synuclein has been linked to the development of Alzheimer's and Parkinson's diseases. We found that all synucleins are GRK substrates, with GRK2 preferentially phosphorylating the alpha and beta isoforms, whereas GRK5 prefers alpha-synuclein as a substrate. GRK-mediated phosphorylation of synuclein is activated by factors that stimulate receptor phosphorylation, such as lipids (all GRKs) and Gbetagamma subunits (GRK2/3), suggesting that GPCR activation may regulate synuclein phosphorylation. GRKs phosphorylate synucleins at a single serine residue within the C-terminal domain. Although the function of synucleins remains largely unknown, recent studies have demonstrated that these proteins can interact with phospholipids and are potent inhibitors of phospholipase D2 (PLD2) in vitro. PLD2 regulates the breakdown of phosphatidylcholine and has been implicated in vesicular trafficking. We found that GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. These findings suggest that GPCRs may be able to indirectly stimulate PLD2 activity via their ability to regulate GRK-promoted phosphorylation of synuclein.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic AMP-Dependent Protein Kinases, http://linkedlifedata.com/resource/pubmed/chemical/G-Protein-Coupled Receptor Kinase 5, http://linkedlifedata.com/resource/pubmed/chemical/GTP-Binding Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Nerve Tissue Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Phospholipase D, http://linkedlifedata.com/resource/pubmed/chemical/Phospholipids, http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases, http://linkedlifedata.com/resource/pubmed/chemical/Synucleins, http://linkedlifedata.com/resource/pubmed/chemical/alpha-Synuclein, http://linkedlifedata.com/resource/pubmed/chemical/beta-Adrenergic Receptor Kinases, http://linkedlifedata.com/resource/pubmed/chemical/phospholipase D2
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
25
pubmed:volume
275
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
26515-22
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:10852916-Amino Acid Sequence, pubmed-meshheading:10852916-Animals, pubmed-meshheading:10852916-Binding Sites, pubmed-meshheading:10852916-Brain, pubmed-meshheading:10852916-Cattle, pubmed-meshheading:10852916-Cyclic AMP-Dependent Protein Kinases, pubmed-meshheading:10852916-G-Protein-Coupled Receptor Kinase 5, pubmed-meshheading:10852916-GTP-Binding Proteins, pubmed-meshheading:10852916-Molecular Sequence Data, pubmed-meshheading:10852916-Nerve Tissue Proteins, pubmed-meshheading:10852916-Phospholipase D, pubmed-meshheading:10852916-Phospholipids, pubmed-meshheading:10852916-Phosphorylation, pubmed-meshheading:10852916-Protein-Serine-Threonine Kinases, pubmed-meshheading:10852916-Structure-Activity Relationship, pubmed-meshheading:10852916-Synucleins, pubmed-meshheading:10852916-alpha-Synuclein, pubmed-meshheading:10852916-beta-Adrenergic Receptor Kinases
pubmed:year
2000
pubmed:articleTitle
Synucleins are a novel class of substrates for G protein-coupled receptor kinases.
pubmed:affiliation
Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.