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. 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 (α, β, γ, and synoretin) are 14-kDa proteins that are highly expressed in brain but also found in numerous other tissues. α-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 α and β isoforms, whereas GRK5 prefers α-synuclein as a substrate. GRK-mediated phosphorylation of synuclein is activated by factors that stimulate receptor phosphorylation, such as lipids (all GRKs) and Gβγ 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. 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 (α, β, γ, and synoretin) are 14-kDa proteins that are highly expressed in brain but also found in numerous other tissues. α-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 α and β isoforms, whereas GRK5 prefers α-synuclein as a substrate. GRK-mediated phosphorylation of synuclein is activated by factors that stimulate receptor phosphorylation, such as lipids (all GRKs) and Gβγ 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. G protein-coupled receptor kinase calmodulin-dependent protein kinase II casein kinase G protein-coupled receptor phospholipase D polymerase chain reaction phosphatidylcholine fast protein liquid chromatography polyacrylamide gel electrophoresis N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine G protein-coupled receptor kinases (GRKs)1 are involved in the regulation of G protein-coupled receptor (GPCR) signaling (1Carman C.V. Benovic J.L. Curr. Opin. Neurobiol. 1998; 8: 335-344Crossref PubMed Scopus (232) Google Scholar, 2Pitcher J.A. Freedman N.J. Lefkowitz R.J. Annu. Rev. Biochem. 1998; 67: 653-692Crossref PubMed Scopus (1060) Google Scholar). GRKs specifically recognize and phosphorylate agonist-occupied GPCRs. Receptor phosphorylation and subsequent binding of another protein, arrestin, uncouples activated receptor from G protein. These events can also promote receptor endocytosis. Internalized receptors are then either dephosphorylated and recycled back to the cell surface or targeted to lysosomes for degradation. The seven mammalian GRKs that have been identified can be divided into three subfamilies based on their overall structural organization and homology: GRK1 (rhodopsin kinase) and GRK7; GRK2 (βARK1) and GRK3 (βARK2); and GRK4, GRK5, and GRK6. Common features shared by the GRKs include a centrally localized catalytic domain of ∼270 amino acids, an N-terminal domain of ∼190 amino acids that has been implicated in receptor interaction and GRK regulation, and a variable length C-terminal domain of 105–233 amino acids that is involved in phospholipid association.Until recently, GPCRs were considered to be the only natural substrates for GRKs. Common protein kinase substrates, such as casein, phosvitin, and synthetic peptides are substrates for GRKs. GPCRs are These suggest that GRKs be highly phosphorylate only activated However, demonstrated that GRKs can also and phosphorylate the protein tubulin J.A. Lefkowitz R.J. 1998; PubMed Scopus Google Scholar, C.V. Benovic J.L. 1998; PubMed Scopus Google Scholar, Biochem. 1998; PubMed Scopus Google Scholar). GRK-mediated phosphorylation of tubulin to be by receptor activation J.A. Lefkowitz R.J. 1998; PubMed Scopus Google Scholar). to phosphorylate the via a interaction J.A. Lefkowitz R.J. PubMed Scopus Google Scholar). Although the role for GRK-mediated phosphorylation of tubulin and the is at these suggest that GRKs may have a broader than and a role in signaling than we the possibility that additional GRK substrates for such substrates, we identified synucleins as a novel of GRK substrates. Synucleins have been linked to the development of such as Alzheimer's and Parkinson's and may be involved in vesicular 1998; 8: PubMed Scopus Google Scholar). We identified the by GRKs in α-synuclein and demonstrated that phosphorylation inhibits the ability of α-synuclein to interact with phospholipids and in of phospholipase D2 role of GRKs in the regulation of signaling is (1Carman C.V. Benovic J.L. Curr. Opin. Neurobiol. 1998; 8: 335-344Crossref PubMed Scopus (232) Google Scholar, 2Pitcher J.A. Freedman N.J. Lefkowitz R.J. Annu. Rev. Biochem. 1998; 67: 653-692Crossref PubMed Scopus (1060) Google Scholar). include and protein demonstrated the of GRK-mediated phosphorylation in receptor However, of GRK function is from and to novel of GRK regulation as as for these the of an domain in GRKs Curr. PubMed Scopus Google to the discovery that GRK2 and GRK3 can specifically interact with activated and signaling C.V. Benovic J.L. PubMed Scopus Google Scholar). that GRKs be able to regulate signaling in a that is of their recent studies have that GRK phosphorylation is to activated receptors as substrates. GRKs can also phosphorylate protein substrates, such as J.A. Lefkowitz R.J. PubMed Scopus Google and tubulin J.A. Lefkowitz R.J. 1998; PubMed Scopus Google Scholar, C.V. Benovic J.L. 1998; PubMed Scopus Google Scholar, Biochem. 1998; PubMed Scopus Google Scholar). Although the role for phosphorylation is phosphorylation of tubulin that GRKs be involved in and The an role in of signaling and is also involved in such as and vesicular trafficking. is that GRK-mediated tubulin phosphorylation a signaling of to receptor or degradation. is also that GRKs be involved in the regulation of signaling and by phosphorylating additional protein for novel GRK substrates, we identified α-synuclein as a protein by GRKs in a brain α-Synuclein to a of proteins amino and and synoretin) 1998; 8: PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). Synucleins are expressed at in the brain and at in and cell such as and α-Synuclein has been linked to the development of a of α-synuclein is a of of Alzheimer's α-Synuclein is also found within of Parkinson's and in the α-synuclein have been linked to the of Parkinson's in PubMed Scopus Google Scholar, 1998; PubMed Scopus Google Scholar). of α-synuclein in in of in and a of in the PubMed Scopus Google Scholar). of the synuclein may a role in the of Google Scholar). the role of synucleins is recent studies have to on their synucleins have the ability to form in 1998; PubMed Scopus Google Scholar). The by synucleins may to the development of diseases. The of synucleins is also Although studies have that synucleins are have demonstrated that synucleins are with 1998; 8: PubMed Scopus Google and other PubMed Scopus Google Scholar). α-Synuclein to interact with interaction is by a N-terminal domain from to binding to lipids 1998; PubMed Scopus Google Scholar). of synuclein's ability to interact with lipids and their with has been that synucleins be involved in vesicular 1998; 8: PubMed Scopus Google studies have identified proteins that can interact with Synucleins can to protein kinase and PubMed Google Scholar). are also potent inhibitors of PLD2 in 1998; PubMed Scopus Google whereas of PubMed Scopus Google Scholar). has been also that synucleins can be by phosphorylation 1998; 8: PubMed Scopus Google Scholar, 1998; PubMed Scopus Google as a and can be in by Biochem. PubMed Scopus Google Scholar). has been that α-synuclein is in and that is dephosphorylated by protein PubMed Scopus Google Scholar). also demonstrated that the casein kinases and can phosphorylate α-synuclein in vitro. However, these kinases phosphorylate other synuclein and regulates phosphorylation and the of synuclein phosphorylation have been we demonstrated that all synucleins are substrates for vitro. GRKs can phosphorylate with α-Synuclein to be the for all whereas and are all GRK2 kinases can also phosphorylate has been both and phosphorylate can phosphorylate but or of α-synuclein with GRKs in demonstrated that GRK2 and GRK5 can also phosphorylate protein in that synuclein phosphorylation by GRKs can be by of the factors that are also to regulate receptor phosphorylation. phosphorylation by all GRKs is by is on the of Gβγ is to be receptor is that activation of receptors by may to synuclein phosphorylation via activated both GRK and synuclein can to the for the in synuclein phosphorylation is possibility is that synucleins a to a for GRKs. possibility is that phospholipids the catalytic activity of GRKs. The the for α-synuclein phosphorylation by the for GRK5 binding to C.V. Benovic J.L. 1998; PubMed Scopus Google and is than the for α-synuclein binding to phospholipids also the phosphorylation of α-synuclein by However, is phospholipids have on α-synuclein phosphorylation by or phosphorylation by phosphorylation of α-synuclein by GRK5 is also activated by is to receptor phosphorylation Benovic J.L. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). that regulation of GRK5 by may be than may only regulate the catalytic activity of GRK5, but may also the of the activation of phosphorylation to be GRK and synuclein phosphorylation by GRK2 in the of whereas GRK5 phosphorylation of on the other is by in a calmodulin-dependent activation in may to phosphorylation of synuclein on kinase is expressed in a cell that synucleins have calmodulin-dependent synuclein phosphorylation may have to phosphorylate a single in the of synucleins in in and in is the residue that is in PubMed Scopus Google Scholar). synuclein these can also be by other such as or C-terminal of synucleins from However, the serine residue by GRKs in synucleins to be all residue is by studies with substrates that GRKs may for the as GRK2 prefers an whereas GRK5 prefers an or Benovic J.L. PubMed Google Scholar). to GRK5 α-synuclein as as both the and of the an role in of the is to α-synuclein and is a for is a for phospholipids also stimulate GRK5 phosphorylation of in and that are from the residue by other kinases that these additional phosphorylation are synucleins a binding to The and function of these is the function of synuclein is that synucleins may a role in the regulation of vesicular and signaling. recent report that α-synuclein may be involved in desensitization of signaling PubMed Scopus Google Scholar). α-synuclein a of and in to However, an with the that α-synuclein is a of by the of the may either a interaction of synuclein with or regulation of an activity such as PLD2. Here we demonstrated that GRK-mediated phosphorylation inhibits both synuclein's ability to interact with lipids and the activity of PLD2. is that the in synuclein's ability to PLD2 is to the of synuclein for can the role of GRK-mediated synuclein phosphorylation in regulation. the of phosphatidylcholine to form and has been to stimulate PubMed Scopus Google Scholar). PLD2 activity also of Curr. PubMed Scopus Google Scholar). of these are involved in receptor activated in can and targeted for endocytosis. GRKs can also phosphorylate of PLD2. of PLD2 of and in receptor additional by synuclein phosphorylation be linked to regulation of from a recent report that α-synuclein can to protein and promote phosphorylation by protein kinase PubMed Scopus Google Scholar). is involved in the regulation of the synuclein residue that is by GRKs the that with is that synuclein phosphorylation interaction with and the of GRK phosphorylation of tubulin may also tubulin The findings that GRKs can interact with proteins such as tubulin and J.A. Lefkowitz R.J. 1998; PubMed Scopus Google Scholar, C.V. Benovic J.L. 1998; PubMed Scopus Google Scholar, Biochem. 1998; PubMed Scopus Google and the of synucleins as GRK substrates suggest an role for GRKs in the regulation of of novel GRK substrates may cellular for these G protein-coupled receptor kinases (GRKs)1 are involved in the regulation of G protein-coupled receptor (GPCR) signaling (1Carman C.V. Benovic J.L. Curr. Opin. Neurobiol. 1998; 8: 335-344Crossref PubMed Scopus (232) Google Scholar, 2Pitcher J.A. Freedman N.J. Lefkowitz R.J. Annu. Rev. Biochem. 1998; 67: 653-692Crossref PubMed Scopus (1060) Google Scholar). GRKs specifically recognize and phosphorylate agonist-occupied GPCRs. Receptor phosphorylation and subsequent binding of another protein, arrestin, uncouples activated receptor from G protein. These events can also promote receptor endocytosis. Internalized receptors are then either dephosphorylated and recycled back to the cell surface or targeted to lysosomes for degradation. The seven mammalian GRKs that have been identified can be divided into three subfamilies based on their overall structural organization and homology: GRK1 (rhodopsin kinase) and GRK7; GRK2 (βARK1) and GRK3 (βARK2); and GRK4, GRK5, and GRK6. Common features shared by the GRKs include a centrally localized catalytic domain of ∼270 amino acids, an N-terminal domain of ∼190 amino acids that has been implicated in receptor interaction and GRK regulation, and a variable length C-terminal domain of 105–233 amino acids that is involved in phospholipid Until recently, GPCRs were considered to be the only natural substrates for GRKs. Common protein kinase substrates, such as casein, phosvitin, and synthetic peptides are substrates for GRKs. GPCRs are These suggest that GRKs be highly phosphorylate only activated However, demonstrated that GRKs can also and phosphorylate the protein tubulin J.A. Lefkowitz R.J. 1998; PubMed Scopus Google Scholar, C.V. Benovic J.L. 1998; PubMed Scopus Google Scholar, Biochem. 1998; PubMed Scopus Google Scholar). GRK-mediated phosphorylation of tubulin to be by receptor activation J.A. Lefkowitz R.J. 1998; PubMed Scopus Google Scholar). to phosphorylate the via a interaction J.A. Lefkowitz R.J. PubMed Scopus Google Scholar). Although the role for GRK-mediated phosphorylation of tubulin and the is at these suggest that GRKs may have a broader than and a role in signaling than we the possibility that additional GRK substrates for such substrates, we identified synucleins as a novel of GRK substrates. Synucleins have been linked to the development of such as Alzheimer's and Parkinson's and may be involved in vesicular 1998; 8: PubMed Scopus Google Scholar). We identified the by GRKs in α-synuclein and demonstrated that phosphorylation inhibits the ability of α-synuclein to interact with phospholipids and in of phospholipase D2 role of GRKs in the regulation of signaling is (1Carman C.V. Benovic J.L. Curr. Opin. Neurobiol. 1998; 8: 335-344Crossref PubMed Scopus (232) Google Scholar, 2Pitcher J.A. Freedman N.J. Lefkowitz R.J. Annu. Rev. Biochem. 1998; 67: 653-692Crossref PubMed Scopus (1060) Google Scholar). include and protein demonstrated the of GRK-mediated phosphorylation in receptor However, of GRK function is from and to novel of GRK regulation as as for these the of an domain in GRKs Curr. PubMed Scopus Google to the discovery that GRK2 and GRK3 can specifically interact with activated and signaling C.V. Benovic J.L. PubMed Scopus Google Scholar). that GRKs be able to regulate signaling in a that is of their recent studies have that GRK phosphorylation is to activated receptors as substrates. GRKs can also phosphorylate protein substrates, such as J.A. Lefkowitz R.J. PubMed Scopus Google and tubulin J.A. Lefkowitz R.J. 1998; PubMed Scopus Google Scholar, C.V. Benovic J.L. 1998; PubMed Scopus Google Scholar, Biochem. 1998; PubMed Scopus Google Scholar). Although the role for phosphorylation is phosphorylation of tubulin that GRKs be involved in and The an role in of signaling and is also involved in such as and vesicular trafficking. is that GRK-mediated tubulin phosphorylation a signaling of to receptor or degradation. is also that GRKs be involved in the regulation of signaling and by phosphorylating additional protein for novel GRK substrates, we identified α-synuclein as a protein by GRKs in a brain α-Synuclein to a of proteins amino and and synoretin) 1998; 8: PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). Synucleins are expressed at in the brain and at in and cell such as and α-Synuclein has been linked to the development of a of α-synuclein is a of of Alzheimer's α-Synuclein is also found within of Parkinson's and in the α-synuclein have been linked to the of Parkinson's in PubMed Scopus Google Scholar, 1998; PubMed Scopus Google Scholar). of α-synuclein in in of in and a of in the PubMed Scopus Google Scholar). of the synuclein may a role in the of Google Scholar). the role of synucleins is recent studies have to on their synucleins have the ability to form in 1998; PubMed Scopus Google Scholar). The by synucleins may to the development of diseases. The of synucleins is also Although studies have that synucleins are have demonstrated that synucleins are with 1998; 8: PubMed Scopus Google and other PubMed Scopus Google Scholar). α-Synuclein to interact with interaction is by a N-terminal domain from to binding to lipids 1998; PubMed Scopus Google Scholar). of synuclein's ability to interact with lipids and their with has been that synucleins be involved in vesicular 1998; 8: PubMed Scopus Google studies have identified proteins that can interact with Synucleins can to protein kinase and PubMed Google Scholar). are also potent inhibitors of PLD2 in 1998; PubMed Scopus Google whereas of PubMed Scopus Google Scholar). has been also that synucleins can be by phosphorylation 1998; 8: PubMed Scopus Google Scholar, 1998; PubMed Scopus Google as a and can be in by Biochem. PubMed Scopus Google Scholar). has been that α-synuclein is in and that is dephosphorylated by protein PubMed Scopus Google Scholar). also demonstrated that the casein kinases and can phosphorylate α-synuclein in vitro. However, these kinases phosphorylate other synuclein and regulates phosphorylation and the of synuclein phosphorylation have been we demonstrated that all synucleins are substrates for vitro. GRKs can phosphorylate with α-Synuclein to be the for all whereas and are all GRK2 kinases can also phosphorylate has been both and phosphorylate can phosphorylate but or of α-synuclein with GRKs in demonstrated that GRK2 and GRK5 can also phosphorylate protein in that synuclein phosphorylation by GRKs can be by of the factors that are also to regulate receptor phosphorylation. phosphorylation by all GRKs is by is on the of Gβγ is to be receptor is that activation of receptors by may to synuclein phosphorylation via activated both GRK and synuclein can to the for the in synuclein phosphorylation is possibility is that synucleins a to a for GRKs. possibility is that phospholipids the catalytic activity of GRKs. The the for α-synuclein phosphorylation by the for GRK5 binding to C.V. Benovic J.L. 1998; PubMed Scopus Google and is than the for α-synuclein binding to phospholipids also the phosphorylation of α-synuclein by However, is phospholipids have on α-synuclein phosphorylation by or phosphorylation by phosphorylation of α-synuclein by GRK5 is also activated by is to receptor phosphorylation Benovic J.L. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). that regulation of GRK5 by may be than may only regulate the catalytic activity of GRK5, but may also the of the activation of phosphorylation to be GRK and synuclein phosphorylation by GRK2 in the of whereas GRK5 phosphorylation of on the other is by in a calmodulin-dependent activation in may to phosphorylation of synuclein on kinase is expressed in a cell that synucleins have calmodulin-dependent synuclein phosphorylation may have to phosphorylate a single in the of synucleins in in and in is the residue that is in PubMed Scopus Google Scholar). synuclein these can also be by other such as or C-terminal of synucleins from However, the serine residue by GRKs in synucleins to be all residue is by studies with substrates that GRKs may for the as GRK2 prefers an whereas GRK5 prefers an or Benovic J.L. PubMed Google Scholar). to GRK5 α-synuclein as as both the and of the an role in of the is to α-synuclein and is a for is a for phospholipids also stimulate GRK5 phosphorylation of in and that are from the residue by other kinases that these additional phosphorylation are synucleins a binding to The and function of these is the function of synuclein is that synucleins may a role in the regulation of vesicular and signaling. recent report that α-synuclein may be involved in desensitization of signaling PubMed Scopus Google Scholar). α-synuclein a of and in to However, an with the that α-synuclein is a of by the of the may either a interaction of synuclein with or regulation of an activity such as PLD2. Here we demonstrated that GRK-mediated phosphorylation inhibits both synuclein's ability to interact with lipids and the activity of PLD2. is that the in synuclein's ability to PLD2 is to the of synuclein for can the role of GRK-mediated synuclein phosphorylation in regulation. the of phosphatidylcholine to form and has been to stimulate PubMed Scopus Google Scholar). PLD2 activity also of Curr. PubMed Scopus Google Scholar). of these are involved in receptor activated in can and targeted for endocytosis. GRKs can also phosphorylate of PLD2. of PLD2 of and in receptor additional by synuclein phosphorylation be linked to regulation of from a recent report that α-synuclein can to protein and promote phosphorylation by protein kinase PubMed Scopus Google Scholar). is involved in the regulation of the synuclein residue that is by GRKs the that with is that synuclein phosphorylation interaction with and the of GRK phosphorylation of tubulin may also tubulin The findings that GRKs can interact with proteins such as tubulin and J.A. Lefkowitz R.J. 1998; PubMed Scopus Google Scholar, C.V. Benovic J.L. 1998; PubMed Scopus Google Scholar, Biochem. 1998; PubMed Scopus Google and the of synucleins as GRK substrates suggest an role for GRKs in the regulation of of novel GRK substrates may cellular for these role of GRKs in the regulation of signaling is (1Carman C.V. Benovic J.L. Curr. Opin. Neurobiol. 1998; 8: 335-344Crossref PubMed Scopus (232) Google Scholar, 2Pitcher J.A. Freedman N.J. Lefkowitz R.J. Annu. Rev. Biochem. 1998; 67: 653-692Crossref PubMed Scopus (1060) Google Scholar). include and protein demonstrated the of GRK-mediated phosphorylation in receptor However, of GRK function is from and to novel of GRK regulation as as for these the of an domain in GRKs Curr. PubMed Scopus Google to the discovery that GRK2 and GRK3 can specifically interact with activated and signaling C.V. Benovic J.L. PubMed Scopus Google Scholar). that GRKs be able to regulate signaling in a that is of their recent studies have that GRK phosphorylation is to activated receptors as substrates. GRKs can also phosphorylate protein substrates, such as J.A. Lefkowitz R.J. PubMed Scopus Google and tubulin J.A. Lefkowitz R.J. 1998; PubMed Scopus Google Scholar, C.V. Benovic J.L. 1998; PubMed Scopus Google Scholar, Biochem. 1998; PubMed Scopus Google Scholar). Although the role for phosphorylation is phosphorylation of tubulin that GRKs be involved in and The an role in of signaling and is also involved in such as and vesicular trafficking. is that GRK-mediated tubulin phosphorylation a signaling of to receptor or degradation. is also that GRKs be involved in the regulation of signaling and by phosphorylating additional protein substrates. for novel GRK substrates, we identified α-synuclein as a protein by GRKs in a brain α-Synuclein to a of proteins amino and and synoretin) 1998; 8: PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). Synucleins are expressed at in the brain and at in and cell such as and α-Synuclein has been linked to the development of a of α-synuclein is a of of Alzheimer's α-Synuclein is also found within of Parkinson's and in the α-synuclein have been linked to the of Parkinson's in PubMed Scopus Google Scholar, 1998; PubMed Scopus Google Scholar). of α-synuclein in in of in and a of in the PubMed Scopus Google Scholar). of the synuclein may a role in the of Google Scholar). the role of synucleins is recent studies have to on their synucleins have the ability to form in 1998; PubMed Scopus Google Scholar). The by synucleins may to the development of diseases. The of synucleins is also Although studies have that synucleins are have demonstrated that synucleins are with 1998; 8: PubMed Scopus Google and other PubMed Scopus Google Scholar). α-Synuclein to interact with interaction is by a N-terminal domain from to binding to lipids 1998; PubMed Scopus Google Scholar). of synuclein's ability to interact with lipids and their with has been that synucleins be involved in vesicular 1998; 8: PubMed Scopus Google Scholar). studies have identified proteins that can interact with Synucleins can to protein kinase and PubMed Google Scholar). are also potent inhibitors of PLD2 in 1998; PubMed Scopus Google whereas of PubMed Scopus Google Scholar). has been also that synucleins can be by phosphorylation 1998; 8: PubMed Scopus Google Scholar, 1998; PubMed Scopus Google as a and can be in by Biochem. PubMed Scopus Google Scholar). has been that α-synuclein is in and that is dephosphorylated by protein PubMed Scopus Google Scholar). also demonstrated that the casein kinases and can phosphorylate α-synuclein in vitro. However, these kinases phosphorylate other synuclein and regulates phosphorylation and the of synuclein phosphorylation have been Here we demonstrated that all synucleins are substrates for vitro. GRKs can phosphorylate with α-Synuclein to be the for all whereas and are all GRK2 kinases can also phosphorylate has been both and phosphorylate can phosphorylate but or of α-synuclein with GRKs in demonstrated that GRK2 and GRK5 can also phosphorylate protein in We that synuclein phosphorylation by GRKs can be by of the factors that are also to regulate receptor phosphorylation. phosphorylation by all GRKs is by is on the of Gβγ is to be receptor is that activation of receptors by may to synuclein phosphorylation via activated both GRK and synuclein can to the for the in synuclein phosphorylation is possibility is that synucleins a to a for GRKs. possibility is that phospholipids the catalytic activity of GRKs. The the for α-synuclein phosphorylation by the for GRK5 binding to C.V. Benovic J.L. 1998; PubMed Scopus Google and is than the for α-synuclein binding to phospholipids also the phosphorylation of α-synuclein by However, is phospholipids have on α-synuclein phosphorylation by or phosphorylation by phosphorylation of α-synuclein by GRK5 is also activated by is to receptor phosphorylation Benovic J.L. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). that regulation of GRK5 by may be than may only regulate the catalytic activity of GRK5, but may also the of the activation of phosphorylation to be GRK and synuclein phosphorylation by GRK2 in the of whereas GRK5 phosphorylation of on the other is by in a calmodulin-dependent activation in may to phosphorylation of synuclein on kinase is expressed in a cell that synucleins have calmodulin-dependent synuclein phosphorylation may have GRKs to phosphorylate a single in the of synucleins in in and in is the residue that is in PubMed Scopus Google Scholar). synuclein these can also be by other such as or C-terminal of synucleins from However, the serine residue by GRKs in synucleins to be all residue is by studies with substrates that GRKs may for the as GRK2 prefers an whereas GRK5 prefers an or Benovic J.L. PubMed Google Scholar). to GRK5 α-synuclein as as both the and of the an role in of the is to α-synuclein and is a for is a for phospholipids also stimulate GRK5 phosphorylation of in and that are from the residue by other kinases that these additional phosphorylation are synucleins a binding to The and function of these is Although the function of synuclein is that synucleins may a role in the regulation of vesicular and signaling. recent report that α-synuclein may be involved in desensitization of signaling PubMed Scopus Google Scholar). α-synuclein a of and in to However, an with the that α-synuclein is a of by the of the may either a interaction of synuclein with or regulation of an activity such as PLD2. Here we demonstrated that GRK-mediated phosphorylation inhibits both synuclein's ability to interact with lipids and the activity of PLD2. is that the in synuclein's ability to PLD2 is to the of synuclein for can the role of GRK-mediated synuclein phosphorylation in regulation. the of phosphatidylcholine to form and has been to stimulate PubMed Scopus Google Scholar). PLD2 activity also of Curr. PubMed Scopus Google Scholar). of these are involved in receptor activated in can and targeted for endocytosis. GRKs can also phosphorylate of PLD2. of PLD2 of and in receptor additional by synuclein phosphorylation be linked to regulation of from a recent report that α-synuclein can to protein and promote phosphorylation by protein kinase PubMed Scopus Google Scholar). is involved in the regulation of the synuclein residue that is by GRKs the that with is that synuclein phosphorylation interaction with and the of GRK phosphorylation of tubulin may also tubulin The findings that GRKs can interact with proteins such as tubulin and J.A. Lefkowitz R.J. 1998; PubMed Scopus Google Scholar, C.V. Benovic J.L. 1998; PubMed Scopus Google Scholar, Biochem. 1998; PubMed Scopus Google and the of synucleins as GRK substrates suggest an role for GRKs in the regulation of of novel GRK substrates may cellular for these We for for and and and for with the