How Does Synaptotagmin Trigger Neurotransmitter Release?

Howard Hughes Medical Institute and Department of Physiology, University of Wisconsin, Madison, WI 53706, USA.
Annual Review of Biochemistry (Impact Factor: 30.28). 02/2008; 77(1):615-41. DOI: 10.1146/annurev.biochem.77.062005.101135
Source: PubMed


Neurotransmitter release at synapses involves a highly specialized form of membrane fusion that is triggered by Ca(2+) ions and is optimized for speed. These observations were established decades ago, but only recently have the molecular mechanisms that underlie this process begun to come into view. Here, we summarize findings obtained from genetically modified neurons and neuroendocrine cells, as well as from reconstituted systems, which are beginning to reveal the molecular mechanism by which Ca(2+)-acting on the synaptic vesicle (SV) protein synaptotagmin I (syt)-triggers rapid exocytosis. This work sheds light not only on presynaptic aspects of synaptic transmission, but also on the fundamental problem of membrane fusion, which has remained a puzzle that has yet to be solved in any biological system.

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    • "Of the membrane lipids studied so far, phosphoinositides have the most well established role in SV endocytosis (Puchkov and Haucke, 2013; Rohrbough and Broadie, 2005). Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P 2 ) modulates SV recycling by recruiting and activating key molecules, such as synaptotagmin I (Chapman, 2008), clathrin adaptor protein AP2 and dynamin-1 (Burger et al., 2000; Di Paolo et al., 2004) to the presynaptic membrane. Genetic deletions of the lipid kinase (phosphatidylinositol phosphate kinase type Ig, PIPK1g) (Di Paolo et al., 2004), or the lipid phosphatase (synaptojanin 1) (Cremona et al., 1999; Mani et al., 2007) that mediate the generation and metabolism of PtdIns(4,5)P 2 , respectively, result in multiple synaptic defects, including impaired SV recycling. "
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    ABSTRACT: Synaptic transmission relies on coordinated coupling of synaptic vesicle (SV) exocytosis and endocytosis. While much attention has focused on characterizing proteins involved in SV recycling, the roles of membrane lipids and their metabolism remain poorly understood. Diacylglycerol, a major signaling lipid produced at synapses during synaptic transmission, is regulated by diacylglycerol kinase (DGK). Here, we report a role for DGKθ in the mammalian CNS in facilitating recycling of presynaptic vesicles at excitatory synapses. Using synaptophysin- and vGlut1-pHluorin optical reporters, we found that acute and chronic deletion of DGKθ attenuated the recovery of SVs following neuronal stimulation. Rescue of recycling kinetics required DGKθ kinase activity. Our data establish a role for DGK catalytic activity at the presynaptic nerve terminal in SV recycling. Altogether, these data suggest that DGKθ supports synaptic transmission during periods of elevated neuronal activity.
    Full-text · Article · Jan 2016 · Cell Reports
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    • "In addition to PI4P 5 0 kinase activation, PA is believed to localize or activate many other proteins involved in exocytosis (Burger et al., 2000; Exton, 2002a,b; Holden et al., 2011; Huang et al., 2011; Jung et al., 1999; Mendonsa and Engebrecht, 2009; Roth, 2008; Yang and Frohman, 2012). For example, anionic lipids bind the C2 domains of synaptotagmin 1 (Syt1) to accelerate membrane fusion and exocytosis (Chapman, 2008; Martens, 2010). Syt1 has been identified to function in cortical granule exocytosis in sea urchins (Leguia et al., 2006). "
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    ABSTRACT: This review emphasizes how lipids regulate membrane fusion and the proteins involved in three developmental stages: oocyte maturation to the fertilizable egg, fertilization and during first cleavage. Decades of work show that phosphatidic acid (PA) releases intracellular calcium, and recent work shows that the lipid can activate Src tyrosine kinase or phospholipase C during Xenopus fertilization. Numerous reports are summarized to show three levels of increase in lipid second messengers inositol 1,4,5-trisphosphate and sn 1,2-diacylglycerol (DAG) during the three different developmental stages. In addition, possible roles for PA, ceramide, lysophosphatidylcholine, plasmalogens, phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, phosphatidylinositol 4,5-bisphosphate, membrane microdomains (rafts) and phosphatidylinositol 3,4,5-trisphosphate in regulation of membrane fusion (acrosome reaction, sperm-egg fusion, cortical granule exocytosis), inositol 1,4,5-trisphosphate receptors, and calcium release are discussed. The role of six lipases involved in generating putative lipid second messengers during fertilization is also discussed: phospholipase D, autotaxin, lipin1, sphingomyelinase, phospholipase C, and phospholipase A2. More specifically, proteins involved in developmental events and their regulation through lipid binding to SH3, SH4, PH, PX, or C2 protein domains is emphasized. New models are presented for PA activation of Src (through SH3, SH4 and a unique domain), that this may be why the SH2 domain of PLCγ is not required for Xenopus fertilization, PA activation of phospholipase C, a role for PA during the calcium wave after fertilization, and that calcium/calmodulin may be responsible for the loss of Src from rafts after fertilization. Also discussed is that the large DAG increase during fertilization derives from phospholipase D production of PA and lipin dephosphorylation to DAG. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Developmental Biology
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    • "Calmodulin-like proteins are found in the genome of certain Gram-positive bacteria [13] [14] [15], in addition to other CaBPs [16]. However, fast Ca 2+ sensors with C2 domains (such as for example synaptotagmins [17]) have not been reported. "
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    ABSTRACT: Molecular cascades of calcium homeostasis and signalling (Ca2+ pumps, channels, cation exchangers, and Ca2 + -binding proteins) emerged in prokaryotes and further developed at the unicellular stage of eukaryote evolution. With progressive evolution, mechanisms of signalling became diversified reflecting multiplication and specialisation of Ca2+ -regulated cellular activities. Recent genomic analysis of organisms from different systematic positions, combined with proteomic and functional probing invigorated expansion in our understanding of the evolution of Ca2+ signalling. Particularly impressive is the consistent role of Ca2 + -ATPases/pumps, calmodulin and calcineurin from very early stages of eukaryotic evolution, although with interspecies differences. Deviations in Ca2+ handling and signalling are observed between vertebrates and flowering plants as well as between protists at the basis of the two systematic categories, Unikonta (for example choanoflagellates) and Bikonta (for example ciliates). Only the B-subunit of calcineurin, for instance, is maintained to regulate highly diversified protein kinases for stress defence in flowering plants, whereas the complete dimeric protein, in vertebrates up to humans, regulates gene transcription, immune-defence and plasticity of the brain. Calmodulin is similarly maintained throughout evolution, but in plants a calmoldulin-like domain is integrated into protein kinase molecules. The eukaryotic cell has inherited and invented many mechanisms to exploit the advantages of signalling by Ca2+, and there is considerable overall similarity in basic processes of Ca2+ regulation and signalling during evolution, although some details may vary.
    Full-text · Article · Mar 2015 · Cell Calcium
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