Pronin AN, et al reorted that synucleins are a novel class of substrates for G protein-coupled
receptor kinases.
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. 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. 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.
NCBI Summary:
Synuclein-gamma is a member of the synuclein family of proteins which are believed to be involved in the pathogenesis of neurodegenerative diseases. High levels of SNCG have been identified in advanced breast carcinomas suggesting a correlation between overexpression of SNCG and breast tumor development.
General function
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Cellular localization
Cytoplasmic
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Ovarian function
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Expression regulated by
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Ovarian localization
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HIGHLY EXPRESSED IN BRAIN, PARTICULARLY IN THE
SUBSTANTIA NIGRA. ALSO EXPRESSED IN THE CORPUS CALLOSUM, HEART,
SKELETAL MUSCLE, OVARY, TESTIS, COLON AND SPLEEN.
Through a survey of
an EST database, Lavedan et al. (1998) found that the SNCG gene may also be
overexpressed in ovarian tumors.