Synapsin I-associated Phosphatidylinositol 3-Kinase Mediates Synaptic Vesicle Delivery to the Readily Releasable Pool

Maintaining synaptic transmission requires replenishment of docked synaptic vesicles within the readily releasable pool (RRP) from synaptic vesicle clusters in the synapsin-bound reserve pool. We show that synapsin forms a complex with phosphatidylinositol 3-kinase (PI 3-kinase) in intact nerve terminals and that synapsin-associated kinase activity increases on depolarization. Disruption of either PI 3-kinase activity or its interaction with synapsin inhibited replenishment of the RRP, but did not affect exocytosis from the RRP. Thus we conclude that a synapsin-associated PI 3-kinase activity plays a role in synaptic vesicle delivery to the RRP. This also suggests that PI 3-kinase contributes to the maintenance of synaptic transmission during periods of high activity, indicating a possible role in synaptic plasticity. Maintaining synaptic transmission requires replenishment of docked synaptic vesicles within the readily releasable pool (RRP) from synaptic vesicle clusters in the synapsin-bound reserve pool. We show that synapsin forms a complex with phosphatidylinositol 3-kinase (PI 3-kinase) in intact nerve terminals and that synapsin-associated kinase activity increases on depolarization. Disruption of either PI 3-kinase activity or its interaction with synapsin inhibited replenishment of the RRP, but did not affect exocytosis from the RRP. Thus we conclude that a synapsin-associated PI 3-kinase activity plays a role in synaptic vesicle delivery to the RRP. This also suggests that PI 3-kinase contributes to the maintenance of synaptic transmission during periods of high activity, indicating a possible role in synaptic plasticity. A typical nerve terminal in the central nervous system contains about 200–250 synaptic vesicles (SVs). 1The abbreviations used are: SV, synaptic vesicle; RRP, readily releasable pool; PI 3-kinase, phosphatidylinositol 3-kinase; SH3, src 3 homology; A1, amphiphysin I; A2, amphiphysin II; GST, glutathione S-transferase; MALDI-TOF MS, matrix-assisted laser desorption/ionization-time of flight mass spectrometry; AP-2, adapter protein-2; GSH, glutathione; EPSC, end plate synoptic current; PI(3,4,5)P3, phosphatidylinositol(3,4,5)triphosphate; IP, immunoprecipitation.1The abbreviations used are: SV, synaptic vesicle; RRP, readily releasable pool; PI 3-kinase, phosphatidylinositol 3-kinase; SH3, src 3 homology; A1, amphiphysin I; A2, amphiphysin II; GST, glutathione S-transferase; MALDI-TOF MS, matrix-assisted laser desorption/ionization-time of flight mass spectrometry; AP-2, adapter protein-2; GSH, glutathione; EPSC, end plate synoptic current; PI(3,4,5)P3, phosphatidylinositol(3,4,5)triphosphate; IP, immunoprecipitation. These can be functionally divided into a small readily releasable pool (RRP) and a large reserve pool. The RRP contains less than 5% of total nerve terminal SVs and is defined morphologically as pre-docked SVs at the active zone and functionally as SVs that are primed and immediately available for the initial rapid phase of neurotransmitter release (1Schikorski T. Stevens C.F. Nat. Neurosci. 2001; 4: 391-395Crossref PubMed Scopus (380) Google Scholar). The remainder constitutes the reserve pool, which ensures that a continual supply of SVs is available for delivery to the RRP and is drawn upon to maintain neurotransmission during periods of intense or prolonged stimulation (2Kuromi H. Kidokoro Y. Neuron. 1998; 20: 917-925Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, 3Mozhayeva M.G. Sara Y. Liu X. Kavalali E.T. J. Neurosci. 2002; 22: 654-665Crossref PubMed Google Scholar, 4Cabin D.E. Shimazu K. Murphy D. Cole N.B. Gottschalk W. McIlwain K.L. Orrison B. Chen A. Ellis C.E. Paylor R. Lu B. Nussbaum R.L. J. Neurosci. 2002; 22: 8797-8807Crossref PubMed Google Scholar). The reserve pool SVs surround the active zone and are clustered together in an actin-based cytoskeletal matrix via an interaction with synapsins (3Mozhayeva M.G. Sara Y. Liu X. Kavalali E.T. J. Neurosci. 2002; 22: 654-665Crossref PubMed Google Scholar, 5Li L. Chin L.S. Shupliakov O. Brodin L. Sihra T.S. Hvalby O. Jensen V. Zheng D. McNamara J.O. Greengard P. Andersen P. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9235-9239Crossref PubMed Scopus (296) Google Scholar). There are five synapsin proteins (Ia, Ib, IIa, IIb, and III) from three genes (I, II, and III) (6Hilfiker S. Pieribone V.A. Czernik A.J. Kao H.T. Augustine G.J. Greengard P. Philos. Trans. R. Soc. Lond-Biol. Sci. 1999; 354: 269-279Crossref PubMed Scopus (436) Google Scholar), which maintain the reserve pool SVs as a cluster and prevent their free dispersal within the terminal. Synapsins I and II control SV replenishment of the RRP, because conditions that disrupt their function result in dispersal or depletion of SV clusters near the active zone and enhance synaptic depression (3Mozhayeva M.G. Sara Y. Liu X. Kavalali E.T. J. Neurosci. 2002; 22: 654-665Crossref PubMed Google Scholar, 5Li L. Chin L.S. Shupliakov O. Brodin L. Sihra T.S. Hvalby O. Jensen V. Zheng D. McNamara J.O. Greengard P. Andersen P. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9235-9239Crossref PubMed Scopus (296) Google Scholar, 7Pieribone V.A. Shupliakov O. Brodin L. Hilfiker-Rothenfluh S. Czernik A.J. Greengard P. Nature. 1995; 375: 493-497Crossref PubMed Scopus (418) Google Scholar). In contrast, disruption of the much less abundant synapsin III does not affect SV clusters and reduces synaptic depression (8Feng J. Chi P. Blanpied T.A. Xu Y. Magarinos A.M. Ferreira A. Takahashi R.H. Kao H.T. McEwen B.S. Ryan T.A. Augustine G.J. Greengard P. J. Neurosci. 2002; 22: 4372-4380Crossref PubMed Google Scholar). SV liberation from clusters within the actin cytomatrix is mediated by the multi-site phosphorylation of synapsin I and II, which decreases their affinity for SVs or actin (6Hilfiker S. Pieribone V.A. Czernik A.J. Kao H.T. Augustine G.J. Greengard P. Philos. Trans. R. Soc. Lond-Biol. Sci. 1999; 354: 269-279Crossref PubMed Scopus (436) Google Scholar). Disruption of synapsin I phosphorylation sites thus reduces the number of SVs undergoing exocytosis (9Chi P. Greengard P. Ryan T.A. Nat. Neurosci. 2001; 4: 1187-1193Crossref PubMed Scopus (283) Google Scholar). It is unknown how liberated SVs translocate to the RRP, and the mechanisms governing entry into the RRP (docking/priming) are incompletely understood (10Waters M.G. Hughson F.M. Traffic. 2000; 1: 588-597Crossref PubMed Scopus (91) Google Scholar). Synapsin I has a C-terminal proline-rich domain that interacts with src homology 3 (SH3) domains present in a large number of proteins, including the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) (6Hilfiker S. Pieribone V.A. Czernik A.J. Kao H.T. Augustine G.J. Greengard P. Philos. Trans. R. Soc. Lond-Biol. Sci. 1999; 354: 269-279Crossref PubMed Scopus (436) Google Scholar, 11Onofri F. Giovedi S. Kao H.T. Valtorta F. Borbone L.B. De Camilli P. Greengard P. Benfenati F. J. Biol. Chem. 2000; 275: 29857-29867Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). A precise role for PI 3-kinase in nerve terminal function has not been established (12Hong S.J. Chang C.C. Br. J. Pharmacol. 1999; 128: 142-148Crossref PubMed Scopus (11) Google Scholar, 13Kelly A. Lynch M.A. Neuropharmacology. 2000; 39: 643-651Crossref PubMed Scopus (131) Google Scholar, 14Suzuki H. Yoshioka K. Maehara T. Guo J.Z. Nonomura Y. Otsuka M. Br. J. Pharmacol. 1998; 125: 1661-1668Crossref PubMed Scopus (7) Google Scholar), despite that its lipid products play numerous roles the actin cytoskeleton and in vesicle trafficking (15Martin T.F. Curr. Opin. Cell Biol. 2001; 13: 493-499Crossref PubMed Scopus (328) Google Scholar, 16Cremona O. De Camilli P. J. Cell Sci. 2001; 114: 1041-1052Crossref PubMed Google Scholar). Synapsin I also connects vesicle traffic with the actin cytoskeleton and the synapsin-p85 in vitro interaction suggests that PI 3-kinase activity might play a role in SV recycling if it occurred in nerve terminals. We examined glutamate release from isolated nerve terminals (synaptosomes) and hippocampal CA1 neurons, and our results implicate synapsin-associated PI 3-kinase activity in the delivery of SVs from the reserve pool to the RRP during periods of high activity or prolonged stimulation. Materials—Wortmannin, LY294002 and protein G were from Sigma, Glutathione-Sepharose from Amersham Biosciences, ωConotoxin-GVIA from Bachem (Saffron-Walden, UK), ωAgatoxin-IVA from the Peptide Institute (Osaka, Japan), p85 antibody from Santa Cruz Biotechnology (Santa Cruz, CA), synapsin I antibody from Upstate Biotechnology (Lake Placid, NY), and the polyclonal synapsin antibody for immunoprecipitations from Mike Browning (Denver, CO). Synthetic peptides Syn I539–553 GAPPAARPPASPSPQ, Syn I566–577 SISGPAPPKVSG, and Syn I585–600 RQGPPQKPPGPAGPIR were synthesized by Auspep (Melbourne, Australia). Penetratin heptapeptide versions (17Fischer P.M. Zhelev N.Z. Wang S. Melville J.E. Fahraeus R. Lane D.P. J. Pept. Res. 2000; 55: 163-172Crossref PubMed Scopus (141) Google Scholar) of the SynI585–600 peptide (RRMKWKK-RQGPPQKPPGPAGPIR) or β-adaptin AP-2 β2624_644 (RRMKWKK-QGDLLGDLLNLDLGPPVNVPQ), were synthesized by Genemed Synthesis (San Francisco, CA). SynI585–600 showed no homology to synapsin II or III. HF-2035 was a gift from H. Hidaka (Nagoya, Japan). The SH3 domain-containing constructs were: Grb2 (pGEX-2T plasmid encoding full-length Grb2) from Roger Daly (Sydney, Australia); p85 (pGEX-2T plasmid encoding the SH3 domain amino acids 2–83 of bovine p85-PI 3-kinase) from Tony Pawson (Toronto, Ontario, Canada); or amphiphysin I (pGEX-2T-Amph 1 SH3 domain, amino acids 588–695) and amphiphysin II (pGEX-2T-Amph 2 SH3 domain, amino acids 516–612) from Pietro De Camilli (Yale, CT). Synaptosome 32P i Labeling and Pull-downs—Synaptosomes from rat brain were labeled with 32Pi (18Robinson P.J. Sontag J.-M. Liu J.P. Fykse E.M. Slaughter C. McMahon H.T. Südhof T.C. Nature. 1993; 365: 163-166Crossref PubMed Scopus (236) Google Scholar, 19Cousin M.A. Tan T.C. Robinson P.J. J. Neurochem. 2001; 76: 105-116Crossref PubMed Scopus (83) Google Scholar), preincubated for 15 min at 37 °C in the absence or presence of drugs and depolarized with 30 mm KCl (S1). Synaptosomes were repolarized in the presence or absence of drug for 7 min before a second KCl stimulus (S2). Synaptosomes (control, S1, repolarization, and S2) were lysed in 25 mm Tris, pH 7.4, containing 1% Triton X-100, 150 mm NaCl, 1 mm EGTA, 2 mm EDTA, 50 mm NaF, 20 μg/ml leupeptin, 1 mm phenylmethylsulfonyl fluoride, and protease inhibitor mixture and centrifuged at 20,442 × g for 15 min at 4 °C. Synapsin I, dynamin I, and synaptojanin were affinity-purified from the supernatant on bacterially expressed glutathione S-transferase (GST) fusion proteins. The GST-p85-SH3 or GST-Grb-2-SH3 domains bound to glutathione-Sepharose (GSH-Sepharose) were mixed with the supernatants for 1 h at 4 °C (19Cousin M.A. Tan T.C. Robinson P.J. J. Neurochem. 2001; 76: 105-116Crossref PubMed Scopus (83) Google Scholar). The washed beads were heated in sample buffer and the released proteins separated by SDS-PAGE. In some experiments total homogenates from rat brain were sequentially three with by three with fusion proteins the SH3 domains of amphiphysin I or II, or domain was mixed with the the was by in the in the MALDI-TOF that bound to the domains were from and to and by MALDI-TOF V.A. Jensen Robinson P.J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). were with the and and a was of or from lysed nerve terminals were as (18Robinson P.J. Sontag J.-M. Liu J.P. Fykse E.M. Slaughter C. McMahon H.T. Südhof T.C. Nature. 1993; 365: 163-166Crossref PubMed Scopus (236) Google Scholar). PI 3-kinase was phosphatidylinositol as the as D. S. M. L. Robinson P.J. 2001; PubMed Scopus Google Scholar). PI activity was was used to released glutamate from from rat Synaptosomes were in either mm or mm mm NaCl, mm mm mm 20 mm mm pH at 37 °C. Synaptosomes were preincubated with 1 or LY294002 for 15 with for or with to either SynI585–600 peptide or to β-adaptin AP-2 for 30 min before stimulation with 30 mm release from the RRP, was in 1 were in with or for 30 and the supernatant the released was glutamate was (19Cousin M.A. Tan T.C. Robinson P.J. J. Neurochem. 2001; 76: 105-116Crossref PubMed Scopus (83) Google Scholar). were from CA1 in from were and at °C for in KCl The 25 mm mm and mm for with pH during was °C. were at was and were if that stimulation was to the via a and was to in stimulation was for min to were stimulation was for were for 15 during which was for the min to a second of stimulation. A of stimulation was to in synaptic SV was and the and release of (19Cousin M.A. Tan T.C. Robinson P.J. J. Neurochem. 2001; 76: 105-116Crossref PubMed Scopus (83) Google Scholar). rat brain F. B. A. Cell Res. 1999; PubMed Scopus Google Scholar) were on in a plate in containing were with 1% and 1 mm for with 2 were with for 20 washed with with with 1% bovine for 15 and with 1% bovine for Synapsin polyclonal (Santa Cruz and PI 3-kinase (Santa Cruz were used at at 4 °C. were washed and for 30 min in the with affinity for synapsin and affinity for a the was a at no Synapsin I and PI in Synapsin with SH3 domain-containing proteins, including I and II, and p85 F. Giovedi S. Kao H.T. Valtorta F. Borbone L.B. De Camilli P. Greengard P. Benfenati F. J. Biol. Chem. 2000; 275: 29857-29867Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). for PI 3-kinase in brain we experiments fusion proteins containing the SH3 domains of amphiphysin I amphiphysin II and proteins by MALDI-TOF mass This was at dynamin I, which the the protein from brain homogenates was the abundant dynamin I The was with no dynamin I was sequentially with the SH3 and synapsins and were present with or synaptojanin and proteins the of was that was an with synapsins and was despite with three SH3 the is SH3 domain proteins and p85 be a protein in nerve terminals. PI 3-kinase in nerve we experiments in or dynamin I, and synapsin Grb2 also synaptojanin and dynamin I, but its with synapsin was the of the was by and by the phosphorylation of the proteins their experiments were in repolarized or in the of protein bound was and not indicating are of their phosphorylation synapsin I and PI 3-kinase a complex in intact nerve we a of of p85 synapsin I, as did of the subunit of PI 3-kinase, synapsin Synapsin and p85 also to SV clusters in in the of with and Thus PI 3-kinase is in the for a role in SV synapsin with an active PI 3-kinase we PI 3-kinase activity in synapsin I A high of activity with synapsin I in nerve terminals. This activity about and was the stimulus was Thus synapsin and PI 3-kinase an active complex in nerve terminals that is by stimulation. PI from the we examined the role of PI 3-kinase activity in neurotransmitter release from is the neurotransmitter in with than of nerve terminals J. 1993; PubMed Scopus Google Scholar). glutamate release was inhibited were preincubated with either 1 or LY294002 inhibitor on glutamate release not on the glutamate J. 1993; PubMed Scopus Google Scholar). The results were with were to min not and of glutamate release been in and release from the RRP or RRP replenishment from reserve pool H.T. J. Neurochem. PubMed Scopus Google Scholar, J. J. Neurochem. PubMed Scopus Google Scholar). or LY294002 inhibited the phase of glutamate release We a number of with mechanisms of for their on the We defined the release from the reserve pool as glutamate released of with glutamate release to from the RRP and a A of than of the RRP, a less than a of SV delivery from the reserve pool. The that were and which the to and This that PI 3-kinase activity be for the delivery of reserve pool SVs to the RRP during prolonged depolarization. that the for PI 3-kinase activity is from the RRP, SVs from the RRP were released by of C. Stevens C.F. Neuron. Full Text Full Text PDF PubMed Scopus Google Scholar). This docked and primed SVs and does not of in the presence or absence of in the release of or an for release from the RRP. were preincubated with or no of glutamate release was either in the presence or absence of PI 3-kinase activity is not for the fusion of SVs that are present in the RRP. The of a phase of glutamate release from with a of SV delivery from the reserve pool. a might during periods of high synaptic transmission in we of from hippocampal CA1 a prolonged of stimulation. a prolonged stimulation at is depletion of the RRP is than replenishment from the reserve pool, to a of D.E. Shimazu K. Murphy D. Cole N.B. Gottschalk W. McIlwain K.L. Orrison B. Chen A. Ellis C.E. Paylor R. Lu B. Nussbaum R.L. J. Neurosci. 2002; 22: 8797-8807Crossref PubMed Google Scholar). stimulation of at for in a of to by the end of stimulation In the neurons, a min of LY294002 stimulation a rapid of and in depression In control and stimulation no in synaptic was no in the of control and at the of indicating LY294002 has no on neurotransmission S. Nat. Neurosci. 2002; PubMed Scopus Google Scholar, M. F. C. R. W. J. Neurosci. 2002; 22: PubMed Google Scholar). This suggests that the RRP in was not by the delivery of reserve pool in a depletion of SVs during a prolonged of stimulation. disruption of synapsins results in a of synaptic depression to of reserve pool SV clusters (3Mozhayeva M.G. Sara Y. Liu X. Kavalali E.T. J. Neurosci. 2002; 22: 654-665Crossref PubMed Google Scholar, 5Li L. Chin L.S. Shupliakov O. Brodin L. Sihra T.S. Hvalby O. Jensen V. Zheng D. McNamara J.O. Greengard P. Andersen P. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9235-9239Crossref PubMed Scopus (296) Google Scholar, M. D. J. Südhof T.C. 1993; Full Text PDF PubMed Scopus Google Scholar). The PI for SV the 3-kinase interaction plays a role in the phase of glutamate We a peptide to used to the synapsin-p85 in vitro F. Giovedi S. Kao H.T. Valtorta F. Borbone L.B. De Camilli P. Greengard P. Benfenati F. J. Biol. Chem. 2000; 275: 29857-29867Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). The peptide the interaction of synapsin I with but not that of dynamin I or synaptojanin A and This is because dynamin I is a of the domain in nerve terminals synapsin I peptides that were A and from the of the of are used for peptide into Pharmacol. Sci. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the of the I interaction in nerve the SynI585–600 peptide was into We the for the C-terminal heptapeptide (17Fischer P.M. Zhelev N.Z. Wang S. Melville J.E. Fahraeus R. Lane D.P. J. Pept. Res. 2000; 55: 163-172Crossref PubMed Scopus (141) Google Scholar) This because PI 3-kinase activity is not The peptide the I interaction but did not affect the dynamin I or synaptojanin The peptide inhibited the phase of glutamate release It did not affect glutamate release not a that nerve terminal was not The of reserve pool glutamate release by was exocytosis was separated into of 4 and of 4 This is in the The peptide was on RRP release by control for of the peptides to the on AP-2 T. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar) were with the AP-2 no on glutamate release and as Thus the that the interaction of PI 3-kinase with synapsin I is for the delivery of SVs to the RRP but not for the fusion of SVs present in the RRP. The of SV delivery is liberation of SVs from the reserve pool (6Hilfiker S. Pieribone V.A. Czernik A.J. Kao H.T. Augustine G.J. Greengard P. Philos. Trans. R. Soc. Lond-Biol. Sci. 1999; 354: 269-279Crossref PubMed Scopus (436) Google Scholar). phosphorylation of synapsin I PI 3-kinase liberation by synapsin either or via a protein kinase as (6Hilfiker S. Pieribone V.A. Czernik A.J. Kao H.T. Augustine G.J. Greengard P. Philos. Trans. R. Soc. Lond-Biol. Sci. 1999; 354: 269-279Crossref PubMed Scopus (436) Google Scholar). we that LY294002 on the phosphorylation of synapsin I in a role for PI 3-kinase in the delivery of SVs from the reserve pool to the RRP for This role is mediated by an PI 3-kinase and synapsin I, via This is the of a of of PI 3-kinase activity in SV are on a of the phase of glutamate release by PI 3-kinase and a peptide that the synapsin-p85 This is not to a in SV recycling because of on SV The and of glutamate release are in and that exocytosis from H.T. J. Neurochem. PubMed Scopus Google Scholar, J. J. Neurochem. PubMed Scopus Google Scholar). A of glutamate release is also in from synapsin I L. Chin L.S. Shupliakov O. Brodin L. Sihra T.S. Hvalby O. Jensen V. Zheng D. McNamara J.O. Greengard P. Andersen P. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9235-9239Crossref PubMed Scopus (296) Google Scholar), the of Thus the interaction of PI 3-kinase with synapsin during phase be for PI 3-kinase to either on the SV or on the The for our results is that of is for the delivery of SVs to the RRP their liberation from the reserve pool. SV delivery has and entry into the RRP. from SV clusters in the reserve pool to the RRP by or mechanisms to a of SVs to release SV entry into the RRP is a mediated by SV at active by a that fusion on the It is that the 3-kinase plays a role in SV entry into the RRP as synapsin is not for (6Hilfiker S. Pieribone V.A. Czernik A.J. Kao H.T. Augustine G.J. Greengard P. Philos. Trans. R. Soc. Lond-Biol. Sci. 1999; 354: 269-279Crossref PubMed Scopus (436) Google Scholar). PI 3-kinase the of vesicle delivery at of vesicle recycling in play III PI 3-kinase PI and of of vesicles at A. R. S. A. J. Murphy C. 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It be in to the of to on the of of PI 3-kinase in SV We Mike Browning for the gift of the H. Hidaka (Nagoya, for and for and on the

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