Presynaptic Trafficking of Synaptotagmin I Is Regulated by Protein Palmitoylation

Protein palmitoylation plays a critical role in sorting and targeting of several proteins to pre- and postsynaptic sites. In this study, we have analyzed the role of palmitoylation in trafficking of synaptotagmin I and its modulation by synaptic activity. We found that palmitoylation of N-terminal cysteines contributed to sorting of synaptotagmin I to an intracellular vesicular compartment at the presynaptic terminal. Presynaptic targeting is a unique feature of N-terminal sequences of synaptotagmin I because the palmitoylated N terminus of synaptotagmin VII failed to localize to presynaptic sites. We also found that palmitate was stably associated with both synaptotagmin I and SNAP-25 and that rapid neuronal depolarization did not affect palmitate turnover on these proteins. However, long-term treatment with drugs that either block synaptic activity or disrupt SNARE complex assembly modulated palmitoylation and accumulation of synaptotagmin I at presynaptic sites. We conclude that palmitoylation is involved in trafficking of specific elements involved in transmitter release and that distinct mechanisms regulate addition and removal of palmitate on select neuronal proteins. Protein palmitoylation plays a critical role in sorting and targeting of several proteins to pre- and postsynaptic sites. In this study, we have analyzed the role of palmitoylation in trafficking of synaptotagmin I and its modulation by synaptic activity. We found that palmitoylation of N-terminal cysteines contributed to sorting of synaptotagmin I to an intracellular vesicular compartment at the presynaptic terminal. Presynaptic targeting is a unique feature of N-terminal sequences of synaptotagmin I because the palmitoylated N terminus of synaptotagmin VII failed to localize to presynaptic sites. We also found that palmitate was stably associated with both synaptotagmin I and SNAP-25 and that rapid neuronal depolarization did not affect palmitate turnover on these proteins. However, long-term treatment with drugs that either block synaptic activity or disrupt SNARE complex assembly modulated palmitoylation and accumulation of synaptotagmin I at presynaptic sites. We conclude that palmitoylation is involved in trafficking of specific elements involved in transmitter release and that distinct mechanisms regulate addition and removal of palmitate on select neuronal proteins. Synaptic transmission requires appropriate protein targeting and assembly of pre- and postsynaptic elements. Protein sorting to distinct domains in polarized cells appears to begin in the Golgi/trans-Golgi network, where proteins can segregate and exit in separate transport vesicles (1Bradke F. Dotti C.G. Biochim. Biophys. Acta. 1998; 1404: 245-258Crossref PubMed Scopus (48) Google Scholar). One mechanism that regulates protein trafficking is palmitoylation, a post-translational modification involving the addition of palmitate, a 16-carbon fatty acid, via a labile thioester linkage (2Resh M.D. Cell. Signal. 1996; 8: 403-412Crossref PubMed Scopus (196) Google Scholar, 3Resh M.D. Biochim. Biophys. Acta. 1999; 1451: 1-16Crossref PubMed Scopus (1083) Google Scholar, 4Dunphy J.T. Linder M.E. Biochim. Biophys. Acta. 1998; 1436: 245-261Crossref PubMed Scopus (317) Google Scholar, 5Linder M.E. Deschenes R.J. Biochemistry. 2003; 42: 4311-4320Crossref PubMed Scopus (185) Google Scholar). In neuronal cells, palmitoylation is critical for sorting of several synaptic proteins (6El-Husseini A.E. Bredt D.S. Nat. Rev. Neurosci. 2002; 3: 791-802Crossref PubMed Scopus (268) Google Scholar). These include the postsynaptic density protein PSD-95, the AMPA 1The abbreviations used are: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; SNARE, soluble NSF attachment protein receptor; APV, dl-amino-5-phosphonopentanoic acid; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; TTX, tetrodotoxin; GFP, green fluorescent protein; HA, hemagglutinin; GABA, γ-aminobutyric acid. receptor-binding protein, and the presynaptic proteins GAP-43 (growth-associated protein of 43 kDa) and GAD-65 (7Zuber M.X. Strittmatter S.M. Fishman M.C. Nature. 1989; 341: 345-348Crossref PubMed Scopus (149) Google Scholar, 8Craven S.E. El-Husseini A.E. Bredt D.S. Neuron. 1999; 22: 497-509Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar, 9El-Husseini A.E. Craven S.E. Chetkovich D.M. Firestein B.L. Schnell E. Aoki C. Bredt D.S. J. Cell Biol. 2000; 148: 159-172Crossref PubMed Scopus (242) Google Scholar, 10DeSouza S. Fu J. States B.A. Ziff E.B. J. Neurosci. 2002; 22: 3493-3503Crossref PubMed Google Scholar, 11Kanaani J. El-Husseini A.E.-D. Aguilera-Moreno A. Diacovo J.M. Bredt D.S. Baekkeskov S. J. Cell Biol. 2002; 158: 1229-1238Crossref PubMed Scopus (60) Google Scholar). Palmitoylation of the AMPA receptor-binding protein and PSD-95 is essential for clustering at the PSD (8Craven S.E. El-Husseini A.E. Bredt D.S. Neuron. 1999; 22: 497-509Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar, 9El-Husseini A.E. Craven S.E. Chetkovich D.M. Firestein B.L. Schnell E. Aoki C. Bredt D.S. J. Cell Biol. 2000; 148: 159-172Crossref PubMed Scopus (242) Google Scholar, 10DeSouza S. Fu J. States B.A. Ziff E.B. J. Neurosci. 2002; 22: 3493-3503Crossref PubMed Google Scholar), whereas palmitoylation of GAD-65 is important for presynaptic targeting (11Kanaani J. El-Husseini A.E.-D. Aguilera-Moreno A. Diacovo J.M. Bredt D.S. Baekkeskov S. J. Cell Biol. 2002; 158: 1229-1238Crossref PubMed Scopus (60) Google Scholar, 12Kanaani J. Diacovo M.J. El-Husseini A.E.-D. Bredt D.S. Baekkeskov S. J. Cell Sci. 2004; 117: 2001-2013Crossref PubMed Scopus (65) Google Scholar). Acylation of several other axonal proteins as well as proteins associated with neurotransmitter release machinery has been recently reported (5Linder M.E. Deschenes R.J. Biochemistry. 2003; 42: 4311-4320Crossref PubMed Scopus (185) Google Scholar, 6El-Husseini A.E. Bredt D.S. Nat. Rev. Neurosci. 2002; 3: 791-802Crossref PubMed Scopus (268) Google Scholar, 13Patterson S.I. Biol. Res. 2002; 35: 139-150Crossref PubMed Scopus (29) Google Scholar). These include members of the synaptotagmin family that regulate synaptic vesicle trafficking and neurotransmitter release (14Chapman E.R. Nat. Rev. Mol. Cell. Biol. 2002; 3: 498-508Crossref PubMed Scopus (378) Google Scholar, 15Südhof T.C. J. Biol. Chem. 2002; 277: 7629-7632Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar). The synaptotagmin family includes 13 members characterized by a unique N-terminal region followed by a transmembrane domain, a cluster of cysteines (the putative palmitoylation site), a variable domain, and two C-terminal C2 domains (15Südhof T.C. J. Biol. Chem. 2002; 277: 7629-7632Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar, 16Chapman E.R. Blasi J. An S. Brose N. Johnston P.A. Südhof T.C. Jahn R. Biochem. Biophys. Res. Commun. 1996; 225: 326-332Crossref PubMed Scopus (61) Google Scholar, 17Veit M. Sollner T.H. Rothman J.E. FEBS Lett. 1996; 385: 119-123Crossref PubMed Scopus (205) Google Scholar, 18Heindel U. Schmidt M.F. Veit M. FEBS Lett. 2003; 544: 57-62Crossref PubMed Scopus (27) Google Scholar). Synaptotagmin I, the most characterized member of the family, is proposed to act as a Ca2+ sensor for regulated exocytosis (19Fernandez-Chacon R. Konigstorfer A. Gerber S.H. Garcia J. Matos M.F. Stevens C.F. Brose N. Rizo J. Rosenmund C. Südhof T.C. Nature. 2001; 410: 41-49Crossref PubMed Scopus (745) Google Scholar). Other abundant members of the family include synaptotagmins III and VII (15Südhof T.C. J. Biol. Chem. 2002; 277: 7629-7632Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar). Interestingly, synaptotagmin I is localized to synaptic vesicles, whereas synaptotagmin VII is localized on the plasma membrane opposite synaptic vesicle docking sites (15Südhof T.C. J. Biol. Chem. 2002; 277: 7629-7632Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar). Despite the striking in the mechanisms involved in sorting of members of the synaptotagmin family SNAP-25 protein of kDa) is palmitoylated protein that is involved in regulated release of at the presynaptic M.C. J. Neurosci. PubMed Google Scholar, E.R. An S. N. Jahn R. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The palmitoylated cysteines the region the and C-terminal involved in with the synaptic that palmitoylation of SNAP-25 on the and that of SNAP-25 the protein to the membrane S. Linder M.E. Mol. Biol. Cell. 1998; PubMed Scopus Google Scholar, S. Linder M.E. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). targeting of SNAP-25 also on with the SNARE protein P.A. Biochem. Biophys. Res. Commun. 1999; PubMed Scopus Google Scholar, M. Biochem. J. 2000; PubMed Scopus Google Scholar). In addition to the role of palmitate in the of protein targeting to and synaptic palmitoylation is also and regulated by specific M. Biochem. Sci. Full Text PDF PubMed Scopus Google Scholar, S.M. Cell Biol. PubMed Scopus Google Scholar). we palmitate turnover on PSD-95 at the (6El-Husseini A.E. Bredt D.S. Nat. Rev. Neurosci. 2002; 3: 791-802Crossref PubMed Scopus (268) Google Scholar). palmitate in an and palmitoylation synaptic of we palmitoylation of synaptotagmin I and two elements involved in regulated neurotransmitter is in neuronal cells and this is modulated by synaptic activity. We that palmitoylation is critical for sorting synaptotagmin I to the intracellular vesicular at presynaptic The presynaptic of the with an in of synaptotagmin I and that palmitoylation is for and sorting to the presynaptic vesicle in in with PSD-95 and palmitate turnover was on synaptotagmin I or SNAP-25 of with long-term of synaptic activity the of palmitoylated SNAP-25 and synaptotagmin In treatment with palmitoylation of synaptotagmin I not These that distinct mechanisms regulate addition and removal of palmitate on select neuronal proteins and that this is regulated by in synaptic activity and with specific elements of the synaptic vesicle release and APV, CNQX, and was was was by whereas was was C. J. J. PubMed Scopus Google Scholar). The I and was protein by and to in and in and with at and of synaptotagmin was by and synaptotagmins I and VII as N-terminal with a or an and and of and C-terminal of synaptotagmin I by and and of SNAP-25 and by and the and sites with in a by and and by with followed by on or with in and in with and of presynaptic used a of of of the the and in for The cells with and in the with for to for at followed by with to and in for at on with and a with a to a Cell and for in with cells for with and for in and cells for variable in with palmitate and synaptic cells with and APV, TTX, or for cells with and in of and the proteins for at was to to the in a of was by at for at with I, and for at the addition of of protein for at with and in with for and analyzed by protein by and to at to with at for of Presynaptic on a a at The of the was to and that the was to for cells with by to and where for of axonal clustering of at to of in of was and the of the of that Cell not a was by and was with the to a of the of polarized protein of and synaptotagmins I and VII in was on two to to cells analyzed for of the of cells analyzed in the of axonal was by the in the axonal These a of axonal axonal and analyzed the to in protein of in clustering of proteins treatment with and protein on at neuronal treatment with the of the in was by the of the at at the both and cells at The for treatment with for in at the and analyzed to in protein of Synaptotagmin in with at for with and with that the N-terminal of synaptotagmin I Synaptic at for at with and for with of the of in was by the of of synaptotagmin I in cells in the of in the of synaptotagmin I in cells and of synaptotagmin I two analyzed the and cells with synaptotagmin I cells on with and with the of synaptotagmin I for on or at with with and with followed by to and of cells with a with a with a at at of used for of on The of was a the in the Palmitoylation Presynaptic of Synaptotagmin that protein palmitoylation is important for trafficking of several synaptic PSD-95, AMPA receptor-binding protein, and GAD-65 (8Craven S.E. El-Husseini A.E. Bredt D.S. Neuron. 1999; 22: 497-509Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar, 9El-Husseini A.E. Craven S.E. Chetkovich D.M. Firestein B.L. Schnell E. Aoki C. Bredt D.S. J. Cell Biol. 2000; 148: 159-172Crossref PubMed Scopus (242) Google Scholar, 10DeSouza S. Fu J. States B.A. Ziff E.B. J. Neurosci. 2002; 22: 3493-3503Crossref PubMed Google Scholar, 11Kanaani J. El-Husseini A.E.-D. Aguilera-Moreno A. Diacovo J.M. Bredt D.S. Baekkeskov S. J. Cell Biol. 2002; 158: 1229-1238Crossref PubMed Scopus (60) Google Scholar). and in the the transmembrane and of synaptotagmin I have been to palmitoylated U. Schmidt M.F. Veit M. FEBS Lett. 2003; 544: 57-62Crossref PubMed Scopus (27) Google Scholar). we palmitoylation to presynaptic targeting of synaptotagmin we and of synaptotagmin I by the palmitoylated cysteines with of palmitoylation of synaptotagmin I in cells In of cysteines and protein palmitoylation that palmitoylation requires cysteines in this palmitoylation is involved in presynaptic targeting of synaptotagmin I, we the of the and of synaptotagmin I in We found that synaptotagmin I was to with a However, the a in of the of axonal to axonal that the of the axonal of synaptotagmin I was In the of to in of the was or of the the and of synaptotagmin I not The presynaptic targeting of synaptotagmin I that palmitoylation to sorting of synaptotagmin I to presynaptic with the in synaptotagmin I with the presynaptic vesicle The synaptic targeting of synaptotagmin I have either sorting to presynaptic vesicles or protein to and of the these we with to the of synaptotagmin I is in the of the and of synaptotagmin I that sorting have contributed to the trafficking of synaptotagmin We palmitoylation regulates trafficking and presynaptic targeting of SNAP-25 accumulation in a compartment the not SNAP-25 in the the of SNAP-25 in the axonal was not axonal and the of palmitoylation to presynaptic of SNAP-25 not not that is important for sorting synaptotagmin I the plasma membrane to an intracellular vesicular compartment A. Rosenmund C. Südhof T.C. Neuron. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). palmitoylation plays a role in sorting synaptotagmin I to an intracellular presynaptic we the of both the and of synaptotagmin I in that the N-terminal of synaptotagmin I with the by A. Rosenmund C. Südhof T.C. Neuron. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), we found that of synaptotagmin I was in synaptotagmin I axonal of synaptotagmin I, the of synaptotagmin I to an intracellular presynaptic vesicle In a in of synaptotagmin I was in the The the in and the of accumulation of synaptotagmin I at presynaptic that palmitoylation is involved in protein and sorting to the presynaptic vesicle this we cells to of the is this cells with the and of synaptotagmin cells for at or with that the of synaptotagmin with and with followed by to and with the by A. Rosenmund C. Südhof T.C. Neuron. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), synaptotagmin I was not on the at both and in an intracellular that of at In was in cells the at both and These that palmitoylation to sorting and of synaptotagmin I the plasma membrane to an intracellular vesicular in cells and to presynaptic in The N-terminal of Synaptotagmin I Synaptotagmin VII to Presynaptic either the or C-terminal region of synaptotagmin I to sequences for presynaptic this we two I and the other I palmitoylation was for presynaptic targeting of the protein, to include the palmitoylation that both and C-terminal sequences palmitoylated of the of axonal to axonal that N-terminal not C-terminal sequences of synaptotagmin I to presynaptic sites The of the in to axonal for I was In the of axonal in I was These that palmitoylation is essential for sorting to axonal that N-terminal sequences of synaptotagmin I for presynaptic Synaptotagmin VII is a member in the family that cysteines that sites for palmitoylation (15Südhof T.C. J. Biol. Chem. 2002; 277: 7629-7632Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar). that synaptotagmin VII was palmitoylated and that its palmitoylation on and synaptotagmin VII in the of these was that for synaptotagmin I and of the palmitoylation that palmitoylation a mechanism involved in sorting members of the synaptotagmin family to axonal we analyzed the N-terminal sequences of synaptotagmin VII VII the palmitoylated cysteines for presynaptic in with I the of the in for VII was and mechanisms involved in presynaptic sorting of members of the synaptotagmin that and assembly of synaptotagmin I regulates membrane exocytosis (14Chapman E.R. Nat. Rev. Mol. Cell. Biol. 2002; 3: 498-508Crossref PubMed Scopus (378) Google Scholar, 15Südhof T.C. J. Biol. Chem. 2002; 277: 7629-7632Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar, Brose N. Jahn R. Südhof T.C. J. Biol. Chem. 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Acta. 1999; 1451: 1-16Crossref PubMed Scopus (1083) Google Scholar, 5Linder M.E. Deschenes R.J. Biochemistry. 2003; 42: 4311-4320Crossref PubMed Scopus (185) Google Scholar). a rapid palmitoylation also important for protein we the addition removal of palmitate on synaptotagmin I and SNAP-25 is at the presynaptic terminal. of synaptotagmin I and SNAP-25 palmitoylation was by and with for and with palmitate for analyzed by of we found in the of palmitoylated synaptotagmin I and SNAP-25 to with palmitate with that synaptotagmin I and SNAP-25 also the In the of palmitate on the postsynaptic protein PSD-95 was The in palmitoylation of PSD-95 have a in palmitoylation or an in protein However, with that PSD-95 protein was the a in PSD-95 palmitoylation is most to a of palmitate a in protein We treatment with an that protein synaptic of PSD-95 and synaptotagmin I that this treatment the of PSD-95 in the of synaptotagmin I was The of in the of synaptotagmin I is with the turnover of palmitate on synaptotagmin I not the turnover of palmitate is to in protein we the turnover of palmitate on localized We found that the of palmitate on GAP-43 was to that of PSD-95 These that the of palmitate with synaptotagmin I and SNAP-25 is a unique feature of proteins associated with the SNARE of Synaptic Palmitoylation of SNAP-25 and Synaptotagmin addition and removal of palmitate on several neuronal and proteins have been proposed to a mechanism for rapid modulation of trafficking of several (6El-Husseini A.E. Bredt D.S. Nat. Rev. Neurosci. 2002; 3: 791-802Crossref PubMed Scopus (268) Google Scholar). of vesicular neurotransmitter release turnover of palmitate, we the of palmitoylated synaptotagmin I, and PSD-95 treatment with neuronal depolarization and rapid neurotransmitter release presynaptic these with for and either with or with for Synaptotagmin I, and PSD-95 and to and in the of palmitoylated proteins these the of to the of proteins. In with (6El-Husseini A.E. Bredt D.S. Nat. Rev. Neurosci. 2002; 3: 791-802Crossref PubMed Scopus (268) Google Scholar), neuronal activity rapid of PSD-95 and However, in the of palmitoylated SNAP-25 and synaptotagmin I was These that of neuronal activity rapid of specific neuronal proteins. a in synaptic activity palmitoylation of synaptotagmin I, we with an that synaptic activity by the However, this treatment did not in a in palmitoylation of synaptotagmin I not an long-term of synaptic activity was used to in protein this to several that block synaptic transmission with These include the and with the was also to block neurotransmitter In these with and APV, TTX, or for cells with for and the on palmitoylation of synaptotagmin I and SNAP-25 analyzed by in in the of palmitoylated synaptotagmin I and The in the of palmitoylated synaptotagmin I also with the of synaptotagmin I treatment with and and in not is important to that that neuronal activity did not have on palmitoylation of synaptotagmin is to a of activity in have the of in the of palmitoylated proteins of neuronal activity. we in palmitoylation treatment with drugs that SNARE proteins and block this either with or with both SNAP-25 and In with the with activity treatment with in palmitoylation of both SNAP-25 and synaptotagmin I In treatment with the of synaptotagmin I with both and palmitoylation of synaptotagmin I not SNAP-25 These opposite and that of palmitate on synaptotagmin I is modulated by with specific elements of the SNARE In this study, we have that palmitoylation contributed to targeting of synaptotagmin I to the presynaptic terminal. synaptotagmin I, the palmitoylated N terminus of synaptotagmin VII was not for targeting to presynaptic sites. striking by of several proteins is that in synaptic activity regulated palmitate turnover on neuronal proteins at that both synaptotagmins I and VII to presynaptic synaptotagmin VII sorting was These in with the synaptotagmin VII sorting to presynaptic sites in Südhof T.C. J. 2003; 22: PubMed Scopus Google Scholar). The presynaptic targeting of synaptotagmin VII is most to in the and density of We also found that N-terminal sequences of synaptotagmin I not synaptotagmin VII for presynaptic that specific presynaptic targeting in a of members of the synaptotagmin In with these by A. Rosenmund C. Südhof T.C. Neuron. 2004; Full Text Full Text PDF PubMed Scopus Google that N-terminal sequences of synaptotagmin I not synaptotagmin VII critical for vesicular targeting in that of synaptotagmin I is the for protein and for synaptotagmin I the plasma membrane to an intracellular vesicular A. Rosenmund C. Südhof T.C. Neuron. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). Palmitoylation has been also to regulate of membrane proteins as (6El-Husseini A.E. Bredt D.S. Nat. Rev. Neurosci. 2002; 3: 791-802Crossref PubMed Scopus (268) Google Scholar). the that synaptotagmin I failed to to a vesicular in We also found that axonal of synaptotagmin I was with that of synaptotagmin The of the also with a to at presynaptic sites. palmitoylation in in protein and in the of synaptotagmin I with synaptic In with a by and P.A. J. Cell Sci. 2000; Google that a the C-terminal of synaptotagmin I is for protein targeting to in These to the of mechanisms for sorting proteins to in cells and to presynaptic in is also that of the transport with distinct of synaptic vesicle Protein sorting the is involved in sorting to presynaptic of palmitoylation and trafficking is for presynaptic targeting of GAD-65 (11Kanaani J. El-Husseini A.E.-D. Aguilera-Moreno A. Diacovo J.M. Bredt D.S. Baekkeskov S. J. Cell Biol. 2002; 158: 1229-1238Crossref PubMed Scopus (60) Google Scholar). we found that SNAP-25 failed to localize to a region that the sorting to the important for the targeting of SNAP-25 to a vesicular a that is involved in of SNAP-25 with other SNARE proteins to presynaptic sites. In synaptotagmin I is a transmembrane protein that the and its palmitoylation is not for sorting to the Synaptotagmin I is a protein that regulates that of synaptotagmin I is a critical in M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. E. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, M. J.T. Neuron. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In N-terminal sequences and the palmitoylated N-terminal cysteines Brose N. Jahn R. Südhof T.C. J. Biol. Chem. Full Text PDF PubMed Google Scholar, M. E. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, C. C. Südhof T.C. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). with the of that synaptotagmin palmitoylated E.R. Blasi J. An S. Brose N. Johnston P.A. Südhof T.C. Jahn R. Biochem. Biophys. Res. Commun. 1996; 225: 326-332Crossref PubMed Scopus (61) Google Scholar). These the of PSD-95, a that is for PSD-95 clustering at the Craven S.E. R. El-Husseini A.E.-D. Bredt D.S. J. Cell Sci. 2003; PubMed Scopus Google Scholar). of synaptotagmin I is for neurotransmitter release M. J.T. Neuron. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), is that also synaptotagmin I clustering in to rapid in Ca2+ neurotransmitter SNAP-25 is palmitoylated protein involved in vesicle Palmitoylation of SNAP-25 is for membrane the of an SNARE complex is of palmitoylation S. Linder M.E. Mol. Biol. Cell. 1998; PubMed Scopus Google Scholar, Schmidt M.F. Veit M. Mol. Cell. 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The of palmitate with synaptotagmin I and SNAP-25 with the of in protein palmitoylation rapid synaptic membrane depolarization that palmitoylation most as a for targeting and assembly of elements involved in neurotransmitter treatment with that block either neurotransmitter release or synaptic transmission palmitoylation of both synaptotagmin I and The postsynaptic most to neuronal and of neurotransmitter However, the of a that regulates the of presynaptic vesicular release of postsynaptic elements. is also that long-term of synaptic transmission have the activity of that regulate addition and removal of palmitate or the of proteins to these activity have protein palmitoylation by the of proteins for palmitoylation protein protein or trafficking to presynaptic with presynaptic accumulation of synaptotagmin I was by that block synaptic activity. These have been to for the in neuronal activity. SNARE proteins an complex of a contributed by membrane and SNAP-25 N. Rev. 1996; PubMed Scopus Google Scholar). complex requires to and the by the of this complex the to transmitter release N. Rev. 1996; PubMed Scopus Google Scholar). two have that palmitoylation of SNAP-25 is by to in P.A. Biochem. Biophys. Res. Commun. 1999; PubMed Scopus Google Scholar, M. Biochem. J. 2000; PubMed Scopus Google Scholar). These at palmitoylation of SNAP-25 is regulated and of the SNARE complex and that fatty a role docking and of synaptic However, that the of palmitoylated SNAP-25 not rapid of transmitter that with SNARE proteins not regulate SNAP-25 palmitoylation in of with synaptotagmin I is essential for vesicle with the plasma membrane M.J. M. Neuron. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). can by specific as and SNAP-25 and other SNARE proteins. that treatment with a that transmitter release by palmitoylation of synaptotagmin I and These with the with other activity In treatment with palmitoylation of synaptotagmin These both drugs SNAP-25 and block neurotransmitter However, treatment with also in the of the of these that of to in neuronal activity have the of palmitate on synaptotagmin I is that several other of the synaptic vesicle the protein, and membrane protein, also palmitoylated (6El-Husseini A.E. Bredt D.S. Nat. Rev. Neurosci. 2002; 3: 791-802Crossref PubMed Scopus (268) Google Scholar). These proteins involved in targeting of synaptic vesicles to the sites of neurotransmitter to the role of palmitoylation in synaptic targeting and assembly of these proteins of neurotransmitter In that rapid palmitate turnover is regulated on a of neuronal proteins and that this can by synaptic activity. Synaptotagmin I palmitoylation appears to to two of that on of neuronal activity and that on with specific elements of the SNARE In addition to the role of palmitoylation in sorting to presynaptic is that is involved in the of vesicular the palmitate also of a and in transmitter We C. Südhof of for synaptotagmin We also and for in neuronal and with

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