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• W2334356172 abstract "Lipids are the most abundant organic compounds in the brain. The brain has a unique lipidome, and changes in lipid concentration, organization, and metabolism are associated with many neuronal diseases. Here, we discuss recent advances in understanding presynaptic membrane lipid organization, centered on illustrative examples of how the lipids themselves regulate membrane trafficking and control protein activity. This insight highlights that presynaptic terminals are membrane-remodeling machines and that cooperation between lipid and protein molecules underlies presynaptic activity. Lipids are the most abundant organic compounds in the brain. The brain has a unique lipidome, and changes in lipid concentration, organization, and metabolism are associated with many neuronal diseases. Here, we discuss recent advances in understanding presynaptic membrane lipid organization, centered on illustrative examples of how the lipids themselves regulate membrane trafficking and control protein activity. This insight highlights that presynaptic terminals are membrane-remodeling machines and that cooperation between lipid and protein molecules underlies presynaptic activity. Lipids are small amphipathic molecules that are insoluble in water and self-assemble into complex structures in an aqueous environment (Figure 1). The nervous system is particularly enriched in lipids and maintains a more diverse lipid composition than other tissues (Bozek et al., 2015Bozek K. Wei Y. Yan Z. Liu X. Xiong J. Sugimoto M. Tomita M. Pääbo S. Sherwood C.C. Hof P.R. et al.Organization and evolution of brain lipidome revealed by large-scale analysis of human, chimpanzee, macaque, and mouse tissues.Neuron. 2015; 85: 695-702Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Sastry, 1985Sastry P.S.S. Lipids of nervous tissue: composition and metabolism.Prog. Lipid Res. 1985; 24: 69-176Crossref PubMed Scopus (424) Google Scholar). This lipid diversity is associated with the evolution of higher cognitive abilities in primates (Bozek et al., 2015Bozek K. Wei Y. Yan Z. Liu X. Xiong J. Sugimoto M. Tomita M. Pääbo S. Sherwood C.C. Hof P.R. et al.Organization and evolution of brain lipidome revealed by large-scale analysis of human, chimpanzee, macaque, and mouse tissues.Neuron. 2015; 85: 695-702Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) and is affected by age and gender (Rappley et al., 2009Rappley I. Myers D.S. Milne S.B. Ivanova P.T. Lavoie M.J. Brown H.A. Selkoe D.J. Lipidomic profiling in mouse brain reveals differences between ages and genders, with smaller changes associated with alpha-synuclein genotype.J. Neurochem. 2009; 111: 15-25Crossref PubMed Scopus (0) Google Scholar, Zhang et al., 1996Zhang Y. Appelkvist E.-L. Kristensson K. Dallner G. The lipid compositions of different regions of rat brain during development and aging.Neurobiol. Aging. 1996; 17: 869-875Abstract Full Text PDF PubMed Scopus (0) Google Scholar), neuronal activity (Kolomiytseva et al., 2008Kolomiytseva I.K. Perepelkina N.I. Zharikova A.D. Popov V.I. Membrane lipids and morphology of brain cortex synaptosomes isolated from hibernating Yakutian ground squirrel.Comp. Biochem. Physiol. B Biochem. Mol. Biol. 2008; 151: 386-391Crossref PubMed Scopus (0) Google Scholar), and stress and trauma (Ji et al., 2012Ji J. Kline A.E. Amoscato A. Samhan-Arias A.K. Sparvero L.J. Tyurin V.A. Tyurina Y.Y. Fink B. Manole M.D. Puccio A.M. et al.Lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of brain injury.Nat. Neurosci. 2012; 15: 1407-1413Crossref PubMed Scopus (0) Google Scholar, Oliveira et al., 2016Oliveira T.G. Chan R.B. Bravo F.V. Miranda A. Silva R.R. Zhou B. Marques F. Pinto V. Cerqueira J.J. Di Paolo G. Sousa N. The impact of chronic stress on the rat brain lipidome.Mol. Psychiatry. 2016; 21: 80-88Crossref PubMed Scopus (0) Google Scholar). Moreover, lipidome changes are associated with a wide spectrum of neurological and psychiatric diseases (Chan et al., 2012Chan R.B. Oliveira T.G. Cortes E.P. Honig L.S. Duff K.E. Small S.A. Wenk M.R. Shui G. Di Paolo G. Comparative lipidomic analysis of mouse and human brain with Alzheimer disease.J. Biol. Chem. 2012; 287: 2678-2688Crossref PubMed Scopus (123) Google Scholar, Cheng et al., 2011Cheng D. Jenner A.M. Shui G. Cheong W.F. Mitchell T.W. Nealon J.R. Kim W.S. McCann H. Wenk M.R. Halliday G.M. Garner B. Lipid pathway alterations in Parkinson’s disease primary visual cortex.PLoS ONE. 2011; 6: e17299Crossref PubMed Scopus (0) Google Scholar, Krebs et al., 2013Krebs C.E. Karkheiran S. Powell J.C. Cao M. Makarov V. Darvish H. Di Paolo G. Walker R.H. Shahidi G.A. Buxbaum J.D. et al.The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures.Hum. Mutat. 2013; 34: 1200-1207Crossref PubMed Scopus (69) Google Scholar, Kurian et al., 2010Kurian M.A. Meyer E. Vassallo G. Morgan N.V. Prakash N. Pasha S. Hai N.A. Shuib S. Rahman F. Wassmer E. et al.Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy.Brain. 2010; 133: 2964-2970Crossref PubMed Scopus (0) Google Scholar, Leoni and Caccia, 2015Leoni V. Caccia C. The impairment of cholesterol metabolism in Huntington disease.Biochim. Biophys. Acta. 2015; 1851: 1095-1105Crossref PubMed Scopus (0) Google Scholar, Martín et al., 2010Martín V. Fabelo N. Santpere G. Puig B. Marín R. Ferrer I. Díaz M. Lipid alterations in lipid rafts from Alzheimer’s disease human brain cortex.J. Alzheimers Dis. 2010; 19: 489-502Crossref PubMed Scopus (0) Google Scholar, Morel et al., 2013Morel E. Chamoun Z. Lasiecka Z.M. Chan R.B. Williamson R.L. Vetanovetz C. Dall’Armi C. Simoes S. Point Du Jour K.S. McCabe B.D. et al.Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system.Nat. Commun. 2013; 4: 2250Crossref PubMed Scopus (0) Google Scholar, Rappley et al., 2009Rappley I. Myers D.S. Milne S.B. Ivanova P.T. Lavoie M.J. Brown H.A. Selkoe D.J. Lipidomic profiling in mouse brain reveals differences between ages and genders, with smaller changes associated with alpha-synuclein genotype.J. Neurochem. 2009; 111: 15-25Crossref PubMed Scopus (0) Google Scholar, Wood et al., 2014Wood P.L. Filiou M.D. Otte D.M. Zimmer A. Turck C.W. Lipidomics reveals dysfunctional glycosynapses in schizophrenia and the G72/G30 transgenic mouse.Schizophr. Res. 2014; 159: 365-369Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Zhu et al., 2015Zhu L. Zhong M. Elder G.A. Sano M. Holtzman D.M. Gandy S. Cardozo C. Haroutunian V. Robakis N.K. Cai D. Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis.Proc. Natl. Acad. Sci. U S A. 2015; 112: 11965-11970Crossref PubMed Scopus (0) Google Scholar) and are paralleled by interest in lipid biomarkers (Mapstone et al., 2014Mapstone M. Cheema A.K. Fiandaca M.S. Zhong X. Mhyre T.R. MacArthur L.H. Hall W.J. Fisher S.G. Peterson D.R. Haley J.M. et al.Plasma phospholipids identify antecedent memory impairment in older adults.Nat. Med. 2014; 20: 415-418Crossref PubMed Scopus (227) Google Scholar) and lipid-modifying therapies (Kamel et al., 2014Kamel F. Goldman S.M. Umbach D.M. Chen H. Richardson G. Barber M.R. Meng C. Marras C. Korell M. Kasten M. et al.Dietary fat intake, pesticide use, and Parkinson’s disease.Parkinsonism Relat. Disord. 2014; 20: 82-87Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Ritchie et al., 2014Ritchie C.W. Bajwa J. Coleman G. Hope K. Jones R.W. Lawton M. Marven M. Passmore P. Souvenaid®: a new approach to management of early Alzheimer’s disease.J Nutr. Health Aging. 2014; 18: 291-299Crossref PubMed Scopus (0) Google Scholar). Positive preclinical findings have already led to trials based on the use of lipid-modifying drugs or specific lipid diets, notably for the treatment of patients with Alzheimer disease or amyotrophic lateral sclerosis (Sparks et al., 2005Sparks D.L. Sabbagh M.N. Connor D.J. Lopez J. Launer L.J. Browne P. Wasser D. Johnson-Traver S. Lochhead J. Ziolwolski C. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results.Arch. Neurol. 2005; 62: 753-757Crossref PubMed Scopus (0) Google Scholar, Li et al., 2007Li G. Larson E.B. Sonnen J.A. Shofer J.B. Petrie E.C. Schantz A. Peskind E.R. Raskind M.A. Breitner J.C. Montine T.J. Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease.Neurology. 2007; 69: 878-885Crossref PubMed Scopus (0) Google Scholar, Sijben et al., 2011Sijben J.W.C. De Wilde M.C. Wieggers R. Groenendijk M. Kamphuis P.J.G.H. A multi nutrient concept to enhance synapse formation and function : science behind a medical food for Alzheimer’s disease.OCL. 2011; 18: 267-270Crossref Google Scholar, Wills et al., 2014Wills A.-M. Hubbard J. Macklin E.A. Glass J. Tandan R. Simpson E.P. Brooks B. Gelinas D. Mitsumoto H. Mozaffar T. et al.MDA Clinical Research NetworkHypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial.Lancet. 2014; 383: 2065-2072Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) (https://ClinicalTrials.gov). Neurons transmit information over long distances and possess a presynaptic terminal that is specialized for neurotransmitter release (Rizzoli, 2014Rizzoli S.O. Synaptic vesicle recycling: steps and principles.EMBO J. 2014; 33: 788-822Crossref PubMed Scopus (0) Google Scholar, Südhof, 2004Südhof T.C. The synaptic vesicle cycle.Annu. Rev. Neurosci. 2004; 27: 509-547Crossref PubMed Scopus (1457) Google Scholar). This terminal is functionally dedicated to membrane remodeling (Figure 1). At synapses, the plasma membrane is extensively restructured to produce synaptic vesicles using endocytic mechanisms, which are sorted and trafficked and then rapidly fuse with the plasma membrane upon opening of voltage-gated ion channels. Although we typically think of protein machinery driving these events, membrane lipid molecules have key roles (Davletov and Montecucco, 2010Davletov B. Montecucco C. Lipid function at synapses.Curr. Opin. Neurobiol. 2010; 20: 543-549Crossref PubMed Scopus (0) Google Scholar, Puchkov and Haucke, 2013Puchkov D. Haucke V. Greasing the synaptic vesicle cycle by membrane lipids.Trends Cell Biol. 2013; 23: 493-503Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar). Synapses are enriched in cholesterol (Puchkov and Haucke, 2013Puchkov D. Haucke V. Greasing the synaptic vesicle cycle by membrane lipids.Trends Cell Biol. 2013; 23: 493-503Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar) and poly-unsaturated fatty acids (PUFAs) (Figure 1) (Marszalek and Lodish, 2005Marszalek J.R. Lodish H.F. Docosahexaenoic acid, fatty acid-interacting proteins, and neuronal function: breastmilk and fish are good for you.Annu. Rev. Cell Dev. Biol. 2005; 21: 633-657Crossref PubMed Scopus (0) Google Scholar, Takamori et al., 2006Takamori S. Holt M. Stenius K. Lemke E.A. Grønborg M. Riedel D. Urlaub H. Schenck S. Brügger B. Ringler P. et al.Molecular anatomy of a trafficking organelle.Cell. 2006; 127: 831-846Abstract Full Text Full Text PDF PubMed Scopus (1020) Google Scholar), and neurotransmission requires several specific trace lipids, including phosphatidylinositol phosphates (PtdInsPs) (Figure 2) (Puchkov and Haucke, 2013Puchkov D. Haucke V. Greasing the synaptic vesicle cycle by membrane lipids.Trends Cell Biol. 2013; 23: 493-503Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar). Furthermore, the presynaptic terminal contains numerous lipid-metabolizing enzymes that locally alter lipid structures and are associated with neurological diseases (Cremona et al., 1999Cremona O. Di Paolo G. Wenk M.R. Lüthi A. Kim W.T. Takei K. Daniell L. Nemoto Y. Shears S.B. Flavell R.A. et al.Essential role of phosphoinositide metabolism in synaptic vesicle recycling.Cell. 1999; 99: 179-188Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar, Di Paolo et al., 2004Di Paolo G. Moskowitz H.S. Gipson K. Wenk M.R. Voronov S. Obayashi M. Flavell R. Fitzsimonds R.M. Ryan T.A. De Camilli P. Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking.Nature. 2004; 431: 415-422Crossref PubMed Scopus (232) Google Scholar, Rohrbough et al., 2004Rohrbough J. Rushton E. Palanker L. Woodruff E. Matthies H.J. Acharya U. Acharya J.K. Broadie K. Ceramidase regulates synaptic vesicle exocytosis and trafficking.J. Neurosci. 2004; 24: 7789-7803Crossref PubMed Scopus (0) Google Scholar). Here we discuss how membrane lipids convey information and actively participate in presynaptic functions via mechanisms that go far beyond simply maintaining a physical barrier. Indeed, on the basis of several specific examples, we highlight how many presynaptic processes are driven by such an intimate, co-dependent, lipid-protein interaction that in the end their functional contribution is inseparably linked. It thus seems that the specialized functions of the presynaptic terminal evolved through cooperation between lipid and protein molecules, and the two work in tandem to drive neurotransmitter release. Presynaptic terminals are highly efficient membrane-remodeling machines. A synaptic vesicle fuses with the plasma membrane within 1 ms of an action potential arriving, and the terminal can maintain rounds of vesicle fusion at frequencies of 100 Hz or higher. Synaptic vesicle exocytosis is spatially organized to occur at active zones that face the clustered neurotransmitter receptors on postsynaptic cells. Active zones contain the core machinery of exocytosis, including the Q-SNAREs Syntaxin 1 and SNAP25, and several core active zone proteins (e.g., RIM, RIM-BP, unc-13, Liprin-alpha-1, and ELKS) that mediate synaptic vesicle docking and priming and recruit voltage-gated calcium channels (Südhof, 2012Südhof T.C. The presynaptic active zone.Neuron. 2012; 75: 11-25Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). A second major round of membrane reorganization occurs post-exocytosis when the terminal re-internalizes membrane (Watanabe et al., 2013Watanabe S. Liu Q. Davis M.W. Hollopeter G. Thomas N. Jorgensen N.B. Jorgensen E.M. Ultrafast endocytosis at Caenorhabditis elegans neuromuscular junctions.eLife. 2013; 2: e00723Crossref Scopus (51) Google Scholar, Zhou et al., 2014Zhou L. McInnes J. Verstreken P. Ultrafast synaptic endocytosis cycles to the center stage.Dev. Cell. 2014; 28: 5-6Abstract Full Text Full Text PDF PubMed Google Scholar). Presynaptic endocytosis is coupled in time and space to synaptic vesicle release, and without this compensation, exocytosis would expand the plasma membrane, proteins and lipids would become mislocalized, and the terminal would eventually lack synaptic vesicles (Kononenko and Haucke, 2015Kononenko N.L. Haucke V. Molecular mechanisms of presynaptic membrane retrieval and synaptic vesicle reformation.Neuron. 2015; 85: 484-496Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). Membrane lipids (Figure 1), especially negatively charged phosphatidylserine (PtdSer) and PtdInsPs in the cytosolic face of the plasma membrane (Figure 2), function at multiple steps of the synaptic vesicle cycle, and the electrostatic charge of these lipids is central to presynaptic exo- and endocytosis and helps couple the two processes. The phosphatidylinositol (PtdIns) head group can be phosphorylated at three different positions, giving rise to seven different PtdInsPs on the basis of the location and number of phosphates (Figure 2A). Although PtdInsPs are low-abundance membrane lipids, some proteins specifically recognize each PtdInsP and thus specifically localize to membrane compartments containing that lipid. PtdIns(4,5)P2 is particularly important in the presynaptic terminal, where it is required for neurotransmission and directly controls the rate of calcium-stimulated exocytosis (Milosevic et al., 2005Milosevic I. Sørensen J.B. Lang T. Krauss M. Nagy G. Haucke V. Jahn R. Neher E. Plasmalemmal phosphatidylinositol-4,5-bisphosphate level regulates the releasable vesicle pool size in chromaffin cells.J. Neurosci. 2005; 25: 2557-2565Crossref PubMed Scopus (128) Google Scholar, Di Paolo et al., 2004Di Paolo G. Moskowitz H.S. Gipson K. Wenk M.R. Voronov S. Obayashi M. Flavell R. Fitzsimonds R.M. Ryan T.A. De Camilli P. Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking.Nature. 2004; 431: 415-422Crossref PubMed Scopus (232) Google Scholar). In the active zones of neuroendocrine PC12 cells, PtdIns(4,5)P2 is unevenly distributed in the plasma membrane, where it concentrates in specific subdomains marked by the Q-SNARE Syntaxin 1A and docked dense core vesicles (Aoyagi et al., 2005Aoyagi K. Sugaya T. Umeda M. Yamamoto S. Terakawa S. Takahashi M. The activation of exocytotic sites by the formation of phosphatidylinositol 4,5-bisphosphate microdomains at syntaxin clusters.J. Biol. Chem. 2005; 280: 17346-17352Crossref PubMed Scopus (0) Google Scholar). The mechanistic basis of this clustering is relatively well understood and is thought to be due to binding between PtdIns(4,5)P2 and basic residues in the juxtamembrane region of Syntaxin 1A that link the transmembrane and SNARE regions (Figure 2B). Indeed, molecular simulations predict that each Syntaxin 1A binds five PtdIns(4,5)P2 molecules (Khelashvili et al., 2012Khelashvili G. Galli A. Weinstein H. Phosphatidylinositol 4,5-biphosphate (PIP(2)) lipids regulate the phosphorylation of syntaxin N-terminus by modulating both its position and local structure.Biochemistry. 2012; 51: 7685-7698Crossref PubMed Scopus (0) Google Scholar). The interaction causes both molecules to co-organize into ∼70 nm clusters detected by super-resolution microscopy using antibodies and probes to detect PtdIns(4,5)P2 (Bar-On et al., 2012Bar-On D. Wolter S. van de Linde S. Heilemann M. Nudelman G. Nachliel E. Gutman M. Sauer M. Ashery U. Super-resolution imaging reveals the internal architecture of nano-sized syntaxin clusters.J. Biol. Chem. 2012; 287: 27158-27167Crossref PubMed Scopus (0) Google Scholar, van den Bogaart et al., 2011van den Bogaart G. Meyenberg K. Risselada H.J. Amin H. Willig K.I. Hubrich B.E. Dier M. Hell S.W. Grubmüller H. Diederichsen U. Jahn R. Membrane protein sequestering by ionic protein-lipid interactions.Nature. 2011; 479: 552-555Crossref PubMed Scopus (218) Google Scholar, Murray and Tamm, 2011Murray D.H. Tamm L.K. Molecular mechanism of cholesterol- and polyphosphoinositide-mediated syntaxin clustering.Biochemistry. 2011; 50: 9014-9022Crossref PubMed Scopus (0) Google Scholar). Consistent with the functional importance of their co-segregation, overexpression of the PtdInsP-phosphatase Synaptojanin-1 (encoded by the Synj1 gene) that notably metabolizes PtdIns(4,5)P2 and PtdIns(3,4,5)P3 (Figure 2A) causes Syntaxin-1A dispersion across the plasma membrane (van den Bogaart et al., 2011van den Bogaart G. Meyenberg K. Risselada H.J. Amin H. Willig K.I. Hubrich B.E. Dier M. Hell S.W. Grubmüller H. Diederichsen U. Jahn R. Membrane protein sequestering by ionic protein-lipid interactions.Nature. 2011; 479: 552-555Crossref PubMed Scopus (218) Google Scholar). The precise stereochemistry of the PtdIns(4,5)P2 head group may be less important for syntaxin 1A organization, and other negatively charged PtdInsPs, including PtdIns(3,4,5)P3, which has even greater negative charge (Figure 2A), could play a similar role (Murray and Tamm, 2011Murray D.H. Tamm L.K. Molecular mechanism of cholesterol- and polyphosphoinositide-mediated syntaxin clustering.Biochemistry. 2011; 50: 9014-9022Crossref PubMed Scopus (0) Google Scholar). At the Drosophila neuromuscular junction, lowering the availability of PtdIns(3,4,5)P3 reduces Syx1A clustering and neurotransmission (Khuong et al., 2013Khuong T.M. Habets R.L.P. Kuenen S. Witkowska A. Kasprowicz J. Swerts J. Jahn R. van den Bogaart G. Verstreken P. Synaptic PI(3,4,5)P3 is required for Syntaxin1A clustering and neurotransmitter release.Neuron. 2013; 77: 1097-1108Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Furthermore, because the Synaptojanin-1 overexpression strategy used to assign the importance of PtdIns(4,5)P2 in mammalian cells is also thought to metabolize PtdIns(3,4,5)P3 (Figure 2A), it is conceivable that PtdIns(3,4,5)P3 is broadly important for this aspect of active zone organization (van den Bogaart et al., 2011van den Bogaart G. Meyenberg K. Risselada H.J. Amin H. Willig K.I. Hubrich B.E. Dier M. Hell S.W. Grubmüller H. Diederichsen U. Jahn R. Membrane protein sequestering by ionic protein-lipid interactions.Nature. 2011; 479: 552-555Crossref PubMed Scopus (218) Google Scholar, Khuong et al., 2013Khuong T.M. Habets R.L.P. Kuenen S. Witkowska A. Kasprowicz J. Swerts J. Jahn R. van den Bogaart G. Verstreken P. Synaptic PI(3,4,5)P3 is required for Syntaxin1A clustering and neurotransmitter release.Neuron. 2013; 77: 1097-1108Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Several proteins responsible for synaptic vesicle priming and docking also bind negatively charged lipids, particularly PtdInsPs, to cluster in the active zone (Martin, 2015Martin T.F.J. PI(4,5)P2-binding effector proteins for vesicle exocytosis.Biochim. Biophys. Acta. 2015; 1851: 785-793Crossref PubMed Scopus (0) Google Scholar). This is largely mediated by structured, positively charged motifs, such as C2, phosphotyrosine-binding or plekstrin homology (PH) domains. C2 domains mediate calcium-dependent and calcium-independent binding to PtdIns(4,5)P2 and are present in cytosolic proteins, including two of the core active zone proteins (unc-13 and RIM) (Südhof, 2012Südhof T.C. The presynaptic active zone.Neuron. 2012; 75: 11-25Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). C2 domains are also present in the synaptic vesicle proteins Synaptotagmin-1 and Doc2-beta that bridge the synaptic vesicle membrane with the plasma membrane (Davletov and Südhof, 1993Davletov B.A. Südhof T.C. A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding.J. Biol. Chem. 1993; 268: 26386-26390Abstract Full Text PDF PubMed Google Scholar, Wen et al., 2011Wen P.J. Osborne S.L. Meunier F.A. Dynamic control of neuroexocytosis by phosphoinositides in health and disease.Prog. Lipid Res. 2011; 50: 52-61Crossref PubMed Scopus (0) Google Scholar). These membrane-bridging interactions may be regulated by other negatively charged lipids, including PtdSer, which can compete with PtdInsPs for protein binding. PtdSer is far more abundant than PtdInsPs in synaptic membranes (Takamori et al., 2006Takamori S. Holt M. Stenius K. Lemke E.A. Grønborg M. Riedel D. Urlaub H. Schenck S. Brügger B. Ringler P. et al.Molecular anatomy of a trafficking organelle.Cell. 2006; 127: 831-846Abstract Full Text Full Text PDF PubMed Scopus (1020) Google Scholar) and directly facilitates exocytosis in PC12 cells (Zhang et al., 2009Zhang Z. Hui E. Chapman E.R. Jackson M.B. Phosphatidylserine regulation of Ca2+-triggered exocytosis and fusion pores in PC12 cells.Mol. Biol. Cell. 2009; 20: 5086-5095Crossref PubMed Scopus (0) Google Scholar). On the basis of in vitro work, PtdSer and PtdInsPs appear to compete for whether Synaptotagmin-1 binds in cis to synaptic vesicle membranes or in trans to the plasma membrane (Chapman, 2002Chapman E.R. Synaptotagmin: a Ca(2+) sensor that triggers exocytosis?.Nat. Rev. Mol. Cell Biol. 2002; 3: 498-508Crossref PubMed Scopus (0) Google Scholar, Vennekate et al., 2012Vennekate W. Schröder S. Lin C.-C. van den Bogaart G. Grunwald M. Jahn R. Walla P.J. Cis- and trans-membrane interactions of synaptotagmin-1.Proc. Natl. Acad. Sci. U S A. 2012; 109: 11037-11042Crossref PubMed Scopus (0) Google Scholar). Although these lipid-protein interactions are often low affinity, the presence of multiple membrane binding domains in a dense network may explain why stable complexes can eventually form at the active zone plasma membrane. Hence, PtdInsPs cluster and regulate both transmembrane and peripheral membrane proteins at presynaptic terminals. PtdInsPs not only help to cluster proteins in the plasma membrane but also appear to regulate the binding between core elements of the presynaptic machinery. The synaptic vesicle R-SNARE, VAMP2, and the calcium sensor Synaptotagmin-1 contain a positively charged region that binds PtdSer and PtdInsPs (Caccin et al., 2015Caccin P. Scorzeto M. Damiano N. Marin O. Megighian A. Montecucco C. The synaptotagmin juxtamembrane domain is involved in neuroexocytosis.FEBS Open Biol. 2015; 5: 388-396Crossref PubMed Google Scholar, Williams et al., 2009Williams D. Vicôgne J. Zaitseva I. McLaughlin S. Pessin J.E. Evidence that electrostatic interactions between vesicle-associated membrane protein 2 and acidic phospholipids may modulate the fusion of transport vesicles with the plasma membrane.Mol. Biol. Cell. 2009; 20: 4910-4919Crossref PubMed Scopus (0) Google Scholar). In the case of VAMP2, interaction with PtdInsPs and PtdSer promotes regulated exocytosis in insulin-secreting beta cells (Williams et al., 2009Williams D. Vicôgne J. Zaitseva I. McLaughlin S. Pessin J.E. Evidence that electrostatic interactions between vesicle-associated membrane protein 2 and acidic phospholipids may modulate the fusion of transport vesicles with the plasma membrane.Mol. Biol. Cell. 2009; 20: 4910-4919Crossref PubMed Scopus (0) Google Scholar). The data suggest that PtdSer and PtdInsPs promote the binding of VAMP2 and Syntaxin-1A by shielding positive charges on either protein as they approach each other during synaptic vesicle docking (Figure 2C). Other lipids also appear to be involved in regulating VAMP2-PtdInsP interactions, including positively charged sphingosine (Darios et al., 2009Darios F. Wasser C. Shakirzyanova A. Giniatullin A. Goodman K. Munoz-Bravo J.L. Raingo J. Jorgačevski J. Kreft M. Zorec R. et al.Sphingosine facilitates SNARE complex assembly and activates synaptic vesicle exocytosis.Neuron. 2009; 62: 683-694Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Quetglas et al., 2000Quetglas S. Leveque C. Miquelis R. Sato K. Seagar M. Ca2+-dependent regulation of synaptic SNARE complex assembly via a calmodulin- and phospholipid-binding domain of synaptobrevin.Proc. Natl. Acad. Sci. U S A. 2000; 97: 9695-9700Crossref PubMed Google Scholar), that can be locally generated by ceramidase cleavage of sphingolipids (Rohrbough et al., 2004Rohrbough J. Rushton E. Palanker L. Woodruff E. Matthies H.J. Acharya U. Acharya J.K. Broadie K. Ceramidase regulates synaptic vesicle exocytosis and trafficking.J. Neurosci. 2004; 24: 7789-7803Crossref PubMed Scopus (0) Google Scholar) (Figure 1A). Thus, by regulating interactions between charged domains, PtdInsPs, PtdSer, and sphingosine can buffer protein-protein interactions to regulate the efficiency of exocytosis. PtdInsPs are multifaceted and also regulate the activity of ion channels that underlie neuronal excitability. PtdIns(4,5)P2, in particular, so strongly controls ion channel conformation that only the proteo-lipid form of a complex conducts ions (Gamper and Shapiro, 2007Gamper N. Shapiro M.S. Regulation of ion transport proteins by membrane phosphoinositides.Nat. Rev. Neurosci. 2007; 8: 921-934Crossref PubMed Scopus (130) Google Scholar). The mechanistic basis of this is best solved for the inward rectifying potassium channels that are responsible for maintaining membrane resting potential. Crystal structures of the Kir2.2 channel in the presence and absence of PtdIns(4,5)P2 (Hansen et al., 2011Hansen S.B. Tao X. MacKinnon R. Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2.Nature. 2011; 477: 495-498Crossref PubMed Scopus (214) Google Scholar, Li et al., 2015Li J. Lü S. Liu Y. Pang C. Chen Y. Zhang S. Yu H. Long M. Zhang H. Logothetis D.E. et al.Identification of the Conformational transition pathway in PIP2 Opening Kir Channels.Sci. Rep. 2015; 5: 11289Crossref PubMed Google Scholar) showed PtdIns(4,5)P2 binding sites located at the interface between the transmembrane and the cytosolic CTD domain of each channel subunit. The presence of PtdIns(4,5)P2 lipids causes a 5–6 Å upward translocation of the entire CTD domain toward the membrane, accompanied by a rotation of the helices that otherwise line the channel gate to swing their hydrophobic side chains away from the ion translocation path (Figure 2D). Consistently, the ability of Kir2 channels to conduct current is inhibited by lipid phosphatases or anti-PtdIns(4,5)P2 antibodies (Gamper and Shapiro, 2007Gamper N. Shapiro M.S. Regulation of ion transport proteins by membrane phosphoinositides.Nat. Rev. Neurosci. 2007; 8: 921-934Crossref PubMed Scopus (130) Google Scholar, Hilgemann et al., 2001Hilgemann D.W. Feng S. Nasuhoglu C. The complex and intriguing lives of PIP2 with ion channels and transporters.Sci. STKE. 2001; 2001: re19Crossref PubMed Scopus (474) Google Scholar, Huang et al., 1998Huang C.L. Feng S. Hilgemann D.W. Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma.Nature. 1998; 391: 803-806Crossref PubMed Scopus (0) Google Scholar). The basic Kir2.2 amino acid residues that bind PtdIns(4,5)P2 are conserved among Kir channels. PtdIns(4,5)P2 binding also alters the conformation of the voltage-gated potassium channel Kv7.1 in response to membrane potential variation (Zaydman et al., 2013Zaydman M.A. Silva J.R. Delaloye K. Li Y. Liang H. Larsson H.P. Shi J. Cui J. Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening.Proc. Natl. Acad. Sci. U S A. 2013; 110: 13" @default.
• W2334356172 created "2016-06-24" @default.
• W2334356172 creator A5040364929 @default.
• W2334356172 creator A5040983698 @default.
• W2334356172 creator A5089999732 @default.
• W2334356172 date "2016-04-01" @default.
• W2334356172 modified "2023-10-17" @default.
• W2334356172 title "Membrane Lipids in Presynaptic Function and Disease" @default.
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