Skip to main content

Part of the book series: Contemporary Neuroscience ((NEUROBIOL))

Abstract

In recent years, the number of lipids implicated in the regulation of the synaptic vesicle exocytosis has risen dramatically. It is now clear that lipids such as the phosphoinositides, arachidonic acid, lysophospholipids, and cholesterol play a critical regulatory role in the processes leading up to exocytosis. Lipids may affect membrane fusion reactions by altering the physical properties of the membrane, recruiting key regulatory proteins, concentrating proteins into exocytic “hot spots,” or modulating protein function allosterically. This chapter discusses the different classes of lipids, the evidence linking them to secretory vesicle exocytosis, how they are thought to act to regulate key steps in the multistep process leading to exocytosis, and future directions.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 179.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 229.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Wiedemann C, Schafer T, Burger MM, Sihra TS. An essential role for a small synaptic vesicle-associated phosphatidylinositol 4-kinase in neurotransmitter release. J Neurosci 1998;18(15):5594–5602.

    CAS  PubMed  Google Scholar 

  2. Takamori S, Holt M, Stenius K, et al. Molecular anatomy of a trafficking organelle. Cell 2006;127(4):831–846.

    Article  CAS  PubMed  Google Scholar 

  3. Milosevic I, Sorensen JB, Lang T, et al. Plasmalemmal phosphatidylinositol-4,5-bisphosphate level regulates the releasable vesicle pool size in chromaffin cells. J Neurosci 2005;25(10):2557–2565.

    Article  CAS  PubMed  Google Scholar 

  4. de Barry J, Janoshazi A, Dupont JL, et al. Functional implication of neuronal calcium sensor-1 and phosphoinositol 4-kinase-beta interaction in regulated exocytosis of PC12 cells. J Biol Chem 2006;281(26):18098–18111.

    Article  PubMed  Google Scholar 

  5. Di Paolo G, Moskowitz HS, Gipson K, et al. Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking. Nature 2004;431(7007):415–422.

    Article  PubMed  Google Scholar 

  6. Cremona O, Di Paolo G, Wenk MR, et al. Essential role of phosphoinositide metabolism in synaptic vesicle recycling. Cell 1999;99(2):179–188.

    Article  CAS  PubMed  Google Scholar 

  7. Wucherpfennig T, Wilsch-Brauninger M, Gonzalez-Gaitan M. Role of Drosophila Rab5 during endosomal trafficking at the synapse and evoked neurotransmitter release. J Cell Biol 2003;161(3):609–624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hawkins PT, Anderson KE, Davidson K, Stephens LR. Signalling through Class I PI3Ks in mammalian cells. Biochem Soc Trans 2006;34(Pt 5):647–662.

    Article  CAS  PubMed  Google Scholar 

  9. Chasserot-Golaz S, Hubert P, Thierse D, et al. Possible involvement of phosphatidylinositol 3-kinase in regulated exocytosis: studies in chromaffin cells with inhibitor LY294002. J Neurochem 1998;70(6):2347–2356.

    Article  Google Scholar 

  10. Martin TF. Phosphoinositides as spatial regulators of membrane traffic. Curr Opin Neurobiol 1997;7(3):331–338.

    Article  CAS  PubMed  Google Scholar 

  11. Wiedemann C, Schafer T, Burger MM. Chromaffin granule-associated phosphatidylinositol 4-kinase activity is required for stimulated secretion. EMBO J 1996;15(9):2094–2101.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Hong SJ, Chang CC. Inhibition of quantal release from motor nerve by wortmannin. Br J Pharmacol 1999;128(1):142–148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rizzoli SO, Betz WJ. Effects of 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one on synaptic vesicle cycling at the frog neuromuscular junction. J Neurosci 2002;22(24):10680–10689.

    CAS  PubMed  Google Scholar 

  14. Meunier FA, Osborne SL, Hammond GR, et al. Phosphatidylinositol 3-kinase C2alpha is essential for ATP-dependent priming of neurosecretory granule exocytosis. Mol Biol Cell 2005;16(10):4841–4851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cousin MA, Malladi CS, Tan TC, Raymond CR, Smillie KJ, Robinson PJ. Synapsin I-associated phosphatidylinositol 3-kinase mediates synaptic vesicle delivery to the readily releasable pool. J Biol Chem 2003;278(31):29065–29071.

    Article  CAS  PubMed  Google Scholar 

  16. Viard P, Butcher AJ, Halet G, et al. PI3K promotes voltage-dependent calcium channel trafficking to the plasma membrane. Nat Neurosci 2004;7(9):939–946.

    Article  CAS  PubMed  Google Scholar 

  17. Osborne SL, Wallis TP, Jimenez JL, Gorman JJ, Meunier FA. Identification of secretory granule phosphatidylinositol 4,5-bisphosphate-interacting proteins using an affinity pulldown strategy. Mol Cell Proteomics 2007;6(7):1158–1169.

    Article  CAS  PubMed  Google Scholar 

  18. Speese S, Petrie M, Schuske K, et al. UNC-31 (CAPS) is required for dense-core vesicle but not synaptic vesicle exocytosis in Caenorhabditis elegans. J Neurosci 2007;27(23):6150–6162.

    Article  CAS  PubMed  Google Scholar 

  19. Speidel D, Bruederle CE, Enk C, et al. CAPS1 regulates catecholamine loading of large dense-core vesicles. Neuron 2005;46(1):75–88.

    Article  CAS  PubMed  Google Scholar 

  20. Haucke V. Phosphoinositide regulation of clathrin-mediated endocytosis. Biochem Soc Trans 2005;33(Pt 6):1285–1289.

    Article  CAS  PubMed  Google Scholar 

  21. Basu J, Betz A, Brose N, Rosenmund C. Munc13-1 C1 domain activation lowers the energy barrier for synaptic vesicle fusion. J Neurosci 2007;27(5):1200–1210.

    Article  CAS  PubMed  Google Scholar 

  22. Bauer CS, Woolley RJ, Teschemacher AG, Seward EP. Potentiation of exocytosis by phospholipase C-coupled G-protein-coupled receptors requires the priming protein Munc13-1. J Neurosci 2007;27(1):212–219.

    Article  CAS  PubMed  Google Scholar 

  23. Rhee SG. Regulation of phosphoinositide-specific phospholipase C. Annu Rev Biochem 2001;70:281–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wierda KDB, Toonen RFG, de Wit H, Brussaard AB, Verhage M. Interdependence of PKC-dependent and PKC-independent pathways for presynaptic plasticity. Neuron 2007;54(2):275–290.

    Article  CAS  PubMed  Google Scholar 

  25. Nili U, de Wit H, Gulyas-Kovacs A, et al. Munc18-1 phosphorylation by protein kinase C potentiates vesicle pool replenishment in bovine chromaffin cells. Neuroscience 2006;143(2):487–500.

    Article  CAS  PubMed  Google Scholar 

  26. Sieburth D, Madison JM, Kaplan JM. PKC-1 regulates secretion of neuropeptides. Nat Neurosci 2007;10(1):49–57.

    Article  CAS  PubMed  Google Scholar 

  27. Feng H, Ren M, Wu SL, Hall DH, Rubin CS. Characterization of a novel protein kinase D: Caenorhabditis elegans DKF-1 is activated by translocation-phosphorylation and regulates movement and growth in vivo. J Biol Chem 2006;281(26):17801–17814.

    Article  CAS  PubMed  Google Scholar 

  28. Huang FD, Matthies HJ, Speese SD, Smith MA, Broadie K. Rolling blackout, a newly identified PIP2-DAG pathway lipase required for Drosophila phototransduction. Nat Neurosci 2004;7(10):1070–1078.

    Article  CAS  PubMed  Google Scholar 

  29. Uchigashima M, Narushima M, Fukaya M, Katona I, Kano M, Watanabe M. Subcellular arrangement of molecules for 2-arachidonoyl-glycerol-mediated retrograde signaling and its physiological contribution to synaptic modulation in the striatum. J Neurosci 2007;27(14):3663–3676.

    Article  CAS  PubMed  Google Scholar 

  30. Llinas R, Sugimori M, Lang EJ, et al. The inositol high-polyphosphate series blocks synaptic transmission by preventing vesicular fusion: a squid giant synapse study. Proc Natl Acad Sci U S A 1994;91(26):12990–12993.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rickman C, Archer DA, Meunier FA, et al. Synaptotagmin interaction with the syntaxin/SNAP-25 dimer is mediated by an evolutionarily conserved motif and is sensitive to inositol hexakisphosphate. J Biol Chem 2004;279(13):12574–12579.

    Article  CAS  PubMed  Google Scholar 

  32. Bader MF, Doussau F, Chasserot-Golaz S, Vitale N, Gasman S. Coupling actin and membrane dynamics during calcium-regulated exocytosis: a role for Rho and ARF GTPases. Biochim Biophys Acta 2004;1742(1–3):37–49.

    Article  CAS  PubMed  Google Scholar 

  33. Zeniou-Meyer M, Zabari N, Ashery U, et al. Phospholipase D1 production of phosphatidic acid at the plasma membrane promotes exocytosis of large dense-core granules at a late stage. J Biol Chem 2007;282(30):21746–21757.

    Article  Google Scholar 

  34. Vitale N, Caumont AS, Chasserot-Golaz S, et al. Phospholipase D1: a key factor for the exocytotic machinery in neuroendocrine cells. EMBO J 2001;20(10):2424–2434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Humeau Y, Vitale N, Chasserot-Golaz S, et al. A role for phospholipase D1 in neurotransmitter release. Proc Natl Acad Sci U S A 2001;98(26):15300–15305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee C, Kim SR, Chung JK, Frohman MA, Kilimann MW, Rhee SG. Inhibition of phospholipase D by amphiphysins. J Biol Chem 2000;275(25):18751–18758.

    Article  CAS  PubMed  Google Scholar 

  37. Rigoni M, Caccin P, Gschmeissner S, et al. Equivalent effects of snake PLA2 neurotoxins and lysophospholipid-fatty acid mixtures. Science 2005;310(5754):1678–1680.

    Article  CAS  PubMed  Google Scholar 

  38. Wei S, Ong WY, Thwin MM, et al. Group IIA secretory phospholipase A2 stimulates exocytosis and neurotransmitter release in pheochromocytoma-12 cells and cultured rat hippocampal neurons. Neuroscience 2003;121(4):891–898.

    Article  CAS  PubMed  Google Scholar 

  39. Gallop JL, Butler PJ, McMahon HT. Endophilin and CtBP/BARS are not acyl transferases in endocytosis or Golgi fission. Nature 2005;438(7068):675–678.

    Article  CAS  PubMed  Google Scholar 

  40. Dietschy JM, Turley SD. Thematic review series: brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 2004;45(8):1375–1397.

    Article  CAS  PubMed  Google Scholar 

  41. Pfrieger FW. Cholesterol homeostasis and function in neurons of the central nervous system. Cell Mol Life Sci 2003;60(6):1158–1171.

    Article  CAS  PubMed  Google Scholar 

  42. Mauch DH, Nagler K, Schumacher S, et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science 2001;294(5545):1354–1357.

    Article  CAS  PubMed  Google Scholar 

  43. Pentchev PG, Comly ME, Kruth HS, et al. A defect in cholesterol esterification in Niemann-Pick disease (type C) patients. Proc Natl Acad Sci 1985;82(23):8247–8251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chamberlain LH, Burgoyne RD, Gould GW. SNARE proteins are highly enriched in lipid rafts in PC12 cells: implications for the spatial control of exocytosis. Proc Natl Acad Sci U S A 2001;98(10):5619–5624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Salaun C, James DJ, Chamberlain LH. Lipid rafts and the regulation of exocytosis. Traffic 2004;5(4):255–264.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Lang T, Bruns D, Wenzel D, et al. SNAREs are concentrated in cholesterol-dependent clusters that define docking and fusion sites for exocytosis. EMBO J 2001;20(9):2202–2213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Taverna E, Saba E, Rowe J, Francolini M, Clementi F, Rosa P. Role of lipid microdomains in P/Q-type calcium channel (Cav2.1) clustering and function in presynaptic membranes. J Biol Chem 2004;279(7):5127–5134.

    Article  CAS  PubMed  Google Scholar 

  48. Chamberlain LH, Burgoyne RD, Gould GW. SNARE proteins are highly enriched in lipid rafts in PC12 cells: implications for the spatial control of exocytosis. Proc Natl Acad Sci U S A 2001;98(10):5619–5624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wasser CR, Ertunc M, Liu X, Kavalali ET. Cholesterol-dependent balance between evoked and spontaneous synaptic vesicle recycling. J Physiol 2007;579(2):413–429.

    Article  CAS  PubMed  Google Scholar 

  50. Gylys KH, Fein JA, Yang F, Miller CA, Cole GM. Increased cholesterol in Abeta-positive nerve terminals from Alzheimer’s disease cortex. Neurobiol Aging 2007;28(1):8–17.

    Article  CAS  PubMed  Google Scholar 

  51. Bajjalieh SM, Martin TF, Floor E. Synaptic vesicle ceramide kinase. A calcium-stimulated lipid kinase that co-purifies with brain synaptic vesicles. J Biol Chem 1989;264(24):14354–14360.

    CAS  PubMed  Google Scholar 

  52. Mitsutake S, Igarashi Y. Calmodulin is involved in the Ca2+-dependent activation of ceramide kinase as a calcium sensor. J Biol Chem 2005;280(49):40436–40441.

    Article  CAS  PubMed  Google Scholar 

  53. Rohrbough J, Rushton E, Palanker L, et al. Ceramidase regulates synaptic vesicle exocytosis and trafficking. J Neurosci 2004;24(36):7789–7803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jeon HJ, Lee DH, Kang MS, et al. Dopamine release in PC12 cells is mediated by Ca(2+)-dependent production of ceramide via sphingomyelin pathway. J Neurochem 2005;95(3):811–820.

    Article  CAS  PubMed  Google Scholar 

  55. Guan XL, He X, Ong WY, Yeo WK, Shui G, Wenk MR. Non-targeted profiling of lipids during kainate-induced neuronal injury. FASEB J 2006;20(8):1152–1161.

    Article  CAS  PubMed  Google Scholar 

  56. Tang N, Ong W Y, Zhang EM, Chen P, Yeo JF. Differential effects of ceramide species on exocytosis in rat PC12 cells. Exp Brain Res 2007;183(2):241–247.

    Article  CAS  PubMed  Google Scholar 

  57. Kajimoto T, Okada T, Yu H, Goparaju SK, Jahangeer S, Nakamura S. Involvement of sphingosine-1-phosphate in glutamate secretion in hippocampal neurons. Mol Cell Biol 2007;27(9):3429–3440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rogasevskaia T, Coorssen JR. Sphingomyelin-enriched microdomains define the efficiency of native Ca(2+)-triggered membrane fusion. J Cell Sci 2006;119(Pt 13):2688–2694.

    Article  CAS  PubMed  Google Scholar 

  59. Huang K, Yanai A, Kang R, et al. Huntingtin-interacting protein HIP14 is a palmitoyl transferase involved in palmitoylation and trafficking of multiple neuronal proteins. Neuron 2004;44(6):977–986.

    Article  CAS  PubMed  Google Scholar 

  60. Veit M. Palmitoylation of the 25–kDa synaptosomal protein (SNAP-25) in vitro occurs in the absence of an enzyme, but is stimulated by binding to syntaxin. Biochem J 2000;345(pt 1):145–151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Veit M, Becher A, Ahnert-Hilger G. Synaptobrevin 2 is palmitoylated in synaptic vesicles prepared from adult, but not from embryonic brain. Mol Cell Neurosci 2000;15(4):408–416.

    Article  CAS  PubMed  Google Scholar 

  62. Veit M, Sollner TH, Rothman JE. Multiple palmitoylation of synaptotagmin and the t-SNARE SNAP-25. FEBS Lett 1996;385(1–2):119–123.

    Article  CAS  PubMed  Google Scholar 

  63. Washbourne P. Greasing transmission: palmitoylation at the synapse. Neuron 2004;44(6):901–902.

    CAS  PubMed  Google Scholar 

  64. Washbourne P, Cansino V, Mathews JR, Graham M, Burgoyne RD, Wilson MC. Cysteine residues of SNAP-25 are required for SNARE disassembly and exocytosis, but not for membrane targeting. Biochem J 2001;357(pt 3):625–634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sorensen JB, Nagy G, Varoqueaux F, et al. Differential control of the releasable vesicle pools by SNAP-25 splice variants and SNAP-23. Cell 2003;114(1):75–86.

    Article  CAS  PubMed  Google Scholar 

  66. Lauritzen L, Hansen HS, Jorgensen MH, Michaelsen KF. The essentiality of long chain n-3 fatty acids in relation to development and function of the brain and retina. Prog Lipid Res 2001;40(1–2):1–94.

    Article  CAS  PubMed  Google Scholar 

  67. Piomelli D, Shapiro E, Feinmark SJ, Schwartz JH. Metabolites of arachidonic acid in the nervous system of Aplysia: possible mediators of synaptic modulation. J Neurosci 1987;7(11):3675–3686.

    CAS  PubMed  Google Scholar 

  68. Piomelli D, Volterra A, Dale N, et al. Lipoxygenase metabolites of arachidonic acid as second messengers for presynaptic inhibition of Aplysia sensory cells. Nature 1987;328(6125):38–43.

    Article  CAS  PubMed  Google Scholar 

  69. Williams JH, Errington ML, Lynch MA, Bliss T V. Arachidonic acid induces a long-term activity-dependent enhancement of synaptic transmission in the hippocampus. Nature 1989;341(6244):739–742.

    Article  CAS  PubMed  Google Scholar 

  70. Schiavo G, Matteoli M, Montecucco C. Neurotoxins affecting neuroexocytosis. Physiol Rev 2000;80(2):717–766.

    CAS  PubMed  Google Scholar 

  71. Morgan A, Burgoyne RD. Relationship between arachidonic acid release and Ca2(+)-dependent exocytosis in digitonin-permeabilized bovine adrenal chromaffin cells. Biochem J 1990;271(3):571–574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lesa GM, Palfreyman M, Hall DH, et al. Long chain polyunsaturated fatty acids are required for efficient neurotransmission in C. elegans. J Cell Sci 2003;116(pt 24):4965–4975.

    Article  CAS  PubMed  Google Scholar 

  73. Latham CF, Osborne SL, Cryle MJ, Meunier FA. Arachidonic acid potentiates exocytosis and allows neuronal SNARE complex to interact with Munc18a. J Neurochem 2007;100(6):1543–1554.

    CAS  PubMed  Google Scholar 

  74. Rickman C, Davletov B. Arachidonic acid allows SNARE complex formation in the presence of Munc18. Chem Biol 2005;12(5):545–553.

    Article  CAS  PubMed  Google Scholar 

  75. Zilly FE, Sorensen JB, Jahn R, Lang T. Munc18-bound syntaxin readily forms SNARE complexes with synaptobrevin in native plasma membranes. PLoS Biol 2006;4(10):e330.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Frederic A. Meunier .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press, a part of Springer Science + Business Media, LLC

About this chapter

Cite this chapter

Osborne, S.L., Meunier, F.A. (2008). Lipids and Secretory Vesicle Exocytosis. In: Wang, ZW. (eds) Molecular Mechanisms of Neurotransmitter Release. Contemporary Neuroscience. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59745-481-0_12

Download citation

Publish with us

Policies and ethics