Mechanism of neurotransmitter release coming into focus
Open accessAbstract
Research for three decades and major recent advances have provided crucial insights into how neurotransmitters are released by Ca 2+ ‐triggered synaptic vesicle exocytosis, leading to reconstitution of basic steps that underlie Ca 2+ ‐dependent membrane fusion and yielding a model that assigns defined functions for central components of the release machinery. The soluble N ‐ethyl maleimide sensitive factor attachment protein receptors (SNAREs) syntaxin‐1, SNAP‐25, and synaptobrevin‐2 form a tight SNARE complex that brings the vesicle and plasma membranes together and is key for membrane fusion. N ‐ethyl maleimide sensitive factor (NSF) and soluble NSF attachment proteins (SNAPs) disassemble the SNARE complex to recycle the SNAREs for another round of fusion. Munc18‐1 and Munc13‐1 orchestrate SNARE complex formation in an NSF‐SNAP‐resistant manner by a mechanism whereby Munc18‐1 binds to synaptobrevin and to a self‐inhibited “closed” conformation of syntaxin‐1, thus forming a template to assemble the SNARE complex, and Munc13‐1 facilitates assembly by bridging the vesicle and plasma membranes and catalyzing opening of syntaxin‐1. Synaptotagmin‐1 functions as the major Ca 2+ sensor that triggers release by binding to membrane phospholipids and to the SNAREs, in a tight interplay with complexins that accelerates membrane fusion. Many of these proteins act as both inhibitors and activators of exocytosis, which is critical for the exquisite regulation of neurotransmitter release. It is still unclear how the actions of these various proteins and multiple other components that control release are integrated and, in particular, how they induce membrane fusion, but it can be expected that these fundamental questions can be answered in the near future, building on the extensive knowledge already available.
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Neurotransmitter release is mediated by the SNARE complex, comprising syntaxin-1, SNAP25, and synaptobrevin, and triggered by the calcium sensor synaptotagmin-1.
“Neurotransmitter release is mediated by the SNARE complex, comprising syntaxin-1, SNAP25, and synaptobrevin, and triggered by the calcium sensor synaptotagmin-1.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [22]
Neurotransmitter release is a multi-step process, not just a single fusion event, because Munc18-1 and Munc13-1 orchestrate SNARE complex formation and vesicle priming.
“The observation that Munc18-1 and Munc13-1 orchestrate SNARE complex formation and vesicle priming reveals that neurotransmitter release is a multi-step process, not just a single fusion event [22].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [22]
The SNARE complex is formed by synaptobrevin (VAMP2), syntaxin-1, and SNAP25, which assemble into a stable four-helix bundle that pulls vesicle and plasma membranes into close proximity, driving membrane fusion.
“This complex is formed by the interaction of three key proteins: synaptobrevin (also known as VAMP2), a v-SNARE located on the synaptic vesicle membrane, and syntaxin-1 and SNAP25, which are t-SNAREs anchored to the presynaptic plasma membrane [22]. These SNARE proteins assemble into a stable four-helix bundle, a structure that physically pulls the vesicle and plasma membranes into close proximity”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [22]
Munc13-1 facilitates SNARE complex assembly by bridging the synaptic vesicle and plasma membranes.
“Munc13-1 further facilitates this assembly process by bridging the synaptic vesicle and plasma membranes.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [22]
Following fusion, the SNARE complex is disassembled by NSF and SNAPs, allowing SNARE proteins to be recycled.
“Following fusion, the SNARE complex is disassembled by the N-ethylmalemaleimide sensitive factor (NSF) and soluble NSF attachment proteins (SNAPs), allowing the SNARE proteins to be recycled for subsequent rounds of neurotransmitter release [22].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [22]
Munc18-1 binds to synaptobrevin and to a "closed" conformation of syntaxin-1, forming a template that guides SNARE complex assembly.
“Munc18-1 binds to synaptobrevin and to a “closed” conformation of syntaxin-1, effectively forming a template that guides SNARE complex assembly [22].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [22]
All four chains are required to form the stable SNARE complex.
“probably because all four chains are required to form the stable complex (86).”
From Computed structures of core eukaryotic protein complexes (2021) · cites this paper as [86]
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Wang, J., Bello, O., Auclair, S., Coleman, J., Pincet, F., Krishnakumar, S. S., Sindelar, C., & Rothman, J. (2014) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1415849111 · Cited by 83 · see citing works
Remote Homology between Munc13 MUN Domain and Vesicle Tethering Complexes
Pei, J., Ma, C., Rizo, J., & Grishin, N. V. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.06.054 · Cited by 83 · see citing works
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Controlling synaptotagmin activity by electrostatic screening
Park, Y., Hernández, J. M., van den Bogaart, G., Ahmed, S., Holt, M., Riedel, D., & Jahn, R. (2012) · Nature Structural &Molecular Biology · doi:10.1038/nsmb.2375 · Cited by 79 · see citing works
Rodríguez-Castañeda, F., Maestre-Martínez, M., Coudevylle, N., Dimova, K. P., Junge, H. J., Lipstein, N., Lee, D., Becker, S., Brose, N., Jahn, O., et al. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.373 · Cited by 77 · see citing works
C-terminal domain of mammalian complexin-1 localizes to highly curved membranes
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Mechanism and function of synaptotagmin-mediated membrane apposition
Hui, E., Gaffaney, J. D., Wang, Z., Johnson, C. P., Evans, C. S., & Chapman, E. R. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2075 · Cited by 76 · see citing works
Munc18‐1 mutations that strongly impair SNARE‐complex binding support normal synaptic transmission
Meijer, M., Burkhardt, P., de Wit, H., Toonen, R. F. G., Fasshauer, D., & Verhage, M. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.72 · Cited by 76 · see citing works
Synaptotagmin C2B Domain Regulates Ca2+-triggered Fusion in Vitro
Gaffaney, J. D., Dunning, F. M., Wang, Z., Hui, E., & Chapman, E. R. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m803355200 · Cited by 75 · see citing works
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Conserved Prefusion Protein Assembly in Regulated Exocytosis
Rickman, C., Jiménez, J. L., Graham, M. E., Archer, D. A., Soloviev, M., Burgoyne, R. D., & Davletov, B. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-07-0620 · Cited by 74 · see citing works
Structure of the Janus-faced C2B domain of rabphilin
Ubach, J., Garcia, J. M., Nittler, M., Südhof, T., & Rizo, J. (1999) · Nature Cell Biology · doi:10.1038/10076 · Cited by 72 · see citing works
Self-citationA C1–C2 Module in Munc13 Inhibits Calcium-Dependent Neurotransmitter Release
Michelassi, F., Liu, H.-W., Hu, Z.-T., & Dittman, J. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.015 · Cited by 72 · see citing works
Genetic analysis of the Complexin trans-clamping model for cross-linking SNARE complexes in vivo
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A role of complexin–lipid interactions in membrane fusion
Seiler, F., Malsam, J., Krause, J. M., & Söllner, T. H. (2009) · FEBS Letters · doi:10.1016/j.febslet.2009.06.025 · Cited by 63 · see citing works
Reconstitution of calcium-mediated exocytosis of dense-core vesicles
Kreutzberger, A. J. B., Kiessling, V., Liang, B., Seelheim, P., Jakhanwal, S., Jahn, R., Castle, J. D., & Tamm, L. K. (2017) · Science Advances · doi:10.1126/sciadv.1603208 · Cited by 62 · see citing works
NMR analysis of the closed conformation of syntaxin-1
Chen, X., Lu, J., Dulubova, I., & Rizo, J. (2008) · Journal of Biomolecular NMR · doi:10.1007/s10858-008-9239-1 · Cited by 61 · see citing works
Self-citationWinter, U., Chen, X., & Fasshauer, D. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.045286 · Cited by 61 · see citing works
A distinct tethering step is vital for vacuole membrane fusion
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Computed structures of core eukaryotic protein complexes
Humphreys, I. R., Pei, J., Baek, M., Krishnakumar, A., Anishchenko, I., Ovchinnikov, S., Zhang, J., Ness, T. J., Banjade, S., Bagde, S. R., et al. (2021) · Science · doi:10.1126/science.abm4805 · Cited by 542 · see citing works
“S26A), probably because all four chains are required to form the stable complex ( 86 ).”
Self-citationMolecular Mechanisms Underlying Neurotransmitter Release
Rizo, J. (2022) · Annual Review of Biophysics · doi:10.1146/annurev-biophys-111821-104732 · Cited by 205 · see citing works
Self-citationBowman, S. L., Bi‐Karchin, J., Le, L., & Marks, M. S. (2019) · Traffic · doi:10.1111/tra.12646 · Cited by 228 · see citing works
“and/or regulating tSNARE conformational changes required for SNARE complex assembly.(441) Accordingly, the RAB27A effector,”
BackgroundDevelopmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum
Guerrini, R., Conti, V., Mantegazza, M., Balestrini, S., Galanopoulou, A. S., & Benfenati, F. (2023) · Physiological Reviews · doi:10.1152/physrev.00063.2021 · Cited by 196 · see citing works
Chaperoning SNARE Folding and Assembly
Zhang, Y., & Hughson, F. M. (2021) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-081820-103615 · Cited by 115 · see citing works
“This calcium-triggered process requires additional regulatory proteins, including Munc13-1, synaptotagmin, complexin, and NSF, whose specific functions have been recently reviewed (39-41).”
BackgroundAyeni, E. A., Aldossary, A. M., Ayejoto, D. A., Gbadegesin, L. A., Alshehri, A. A., Alfassam, H. A., Afewerky, H. K., Almughem, F. A., Saidu, M. B., & Tawfik, E. A. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph191912495 · Cited by 114 · see citing works
“Neurotransmitters are endogenous chemicals that allow communication between neurons and contribute to daily activities and functions of the body [35].”
BackgroundMembrane bridging by Munc13-1 is crucial for neurotransmitter release
Quade, B., Camacho, M., Zhao, X., Orlando, M., Trimbuch, T., Xu, J., Li, W., Nicastro, D., Rosenmund, C., & Rizo, J. (2019) · eLife · doi:10.7554/elife.42806 · Cited by 108 · see citing works
“…and C2 domains at both ends of the Munc13 MUN domain may have occurred during evolution to provide opportunities for regulation of this membrane-bridging activity, as exquisite regulation is a hallmark of neurotransmitter release and Munc13-1 acts as a master regulator of this process (Rizo, 2018).”
InfluentialSelf-citationThe pre-synaptic fusion machinery
Brünger, A. T., Choi, U. B., Lai, Y., Leitz, J., White, K. I., & Zhou, Q. (2019) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2019.03.007 · Cited by 104 · see citing works
“Of course, it possible that the activation relates to the interactions between Munc13 and the membrane as opposed to a conformational change in Munc13 [62].”
Rajagopalan, V., Venkataraman, S., Rajendran, D. S., Vaidyanathan, V. K., Vaithyanathan, V. K., & Rangasamy, G. (2023) · Environmental Research · doi:10.1016/j.envres.2023.115724 · Cited by 90 · see citing works
The Gut–Brain Axis in Schizophrenia: The Implications of the Gut Microbiome and SCFA Production
Ju, S., Shin, Y., Han, S., Kwon, J., Choi, T. G., Kang, I., & Kim, S. S. (2023) · Nutrients · doi:10.3390/nu15204391 · Cited by 95 · see citing works
“Neurotransmitters are naturally occurring chemicals that facilitate communication be-tween neurons throughout the body and play a vital role in regulating various physiological processes [67].”
BackgroundKádková, A., Radecke, J., & Sørensen, J. B. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.09.020 · Cited by 89 · see citing works
An overview of the synaptic vesicle lipid composition
Binotti, B., Jahn, R., & Pérez-Lara, Á. (2021) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2021.108966 · Cited by 86 · see citing works
“instance, is essential for the priming of synaptic vesicles at the AZs, owing to the activation of protein kinase C (PKC) and Munc 13 [97,98], while PA would facilitate the functional interactions among SNARE and SNARE chaperones [99].”
BackgroundSNARE assembly enlightened by cryo-EM structures of a synaptobrevin–Munc18-1–syntaxin-1 complex
Stepien, K. P., Xu, J.-J., Zhang, X.-W., Bai, X.-C., & Rizo, J. (2022) · bioRxiv · doi:10.1126/sciadv.abo5272 · Cited by 68 · see citing works
“(A-H) Normalized histograms of mass distributions observed for samples containing the indicated concentrations of WT or mutant Munc18-1 (M18) plus WT or mutant syntaxin-1(2-253) (Syx) (A-D), or mutant Munc18-1 plus SyxLE/Syb with or without the M183A or D184P mutations (E-H).”
InfluentialSelf-citationCalcium-dependent docking of synaptic vesicles
Silva, M., Tran, V., & Marty, A. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2021.04.003 · Cited by 82 · see citing works
Unraveling the complexity of human brain: Structure, function in healthy and disease states
Sultana, O. F., Bandaru, M., Islam, M. A., & Reddy, P. H. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102414 · Cited by 88 · see citing works
Structure of membrane tethers and their role in fusion
Ungermann, C., & Kümmel, D. (2019) · Traffic · doi:10.1111/tra.12655 · Cited by 82 · see citing works
The RAB3-RIM pathway is essential for the release of neuromodulators
Persoon, C. M., Hoogstraaten, R. I., Nassal, J., van Weering, J. V., Kaeser, P. S., Toonen, R., & Verhage, M. (2019) · Neuron · doi:10.1016/j.neuron.2019.09.015 · Cited by 73 · see citing works
“MUNC13 is proposed to tether synaptic vesicles by bridging between vesicle and plasma membrane via its C2C domain and C1/C2B domains, respectively (Liu et al., 2016; Rizo, 2018).”
Bonnycastle, K., Davenport, E. C., & Cousin, M. A. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15035 · Cited by 74 · see citing works
“After filling, SVs physically attach to a dense network of proteins at the active zone (Gundelfinger & Fejtova, 2012) and are then rendered fusogenic via a priming reaction (Brunger, Choi, Lai, Leitz, & Zhou, 2018; Rizo, 2018).”
BackgroundUnc13: A multifunctional synaptic marvel
Dittman, J. (2019) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2018.12.011 · Cited by 78 · see citing works
The Role of Kv7.2 in Neurodevelopment: Insights and Gaps in Our Understanding
Dirkx, N., Miceli, F., Taglialatela, M., & Weckhuysen, S. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.570588 · Cited by 77 · see citing works
Multiple factors maintain assembled trans-SNARE complexes in the presence of NSF and αSNAP
Prinslow, E. A., Stepien, K. P., Pan, Y.-Z., Xu, J., & Rizo, J. (2019) · eLife · doi:10.7554/elife.38880 · Cited by 76 · see citing works
“Extensive research has shown that these steps are exquisitely regulated by a sophisticated protein machinery and has led to defined models for the functions of key components from this machinery (Brunger et al., 2018; Jahn and Fasshauer, 2012; Rizo, 2018; Südhof and Rothman, 2009).”
BackgroundInfluentialSelf-citationVoleti, R., Jaczynska, K., & Rizo, J. (2020) · eLife · doi:10.7554/elife.57154 · Cited by 76 · see citing works
“Extensive research has allowed reconstitution of basic features of synaptic vesicle fusion with the central components of the neurotransmitter release machinery (Liu et al., 2016; Ma et al., 2013) and led to defined models for their functions (Brunger et al., 2018; Rizo, 2018).”
BackgroundSelf-citationSiddig, S., Aufmkolk, S., Doose, S., Jobin, M., Werner, C. D., Sauer, M., & Calebiro, D. (2020) · Science Advances · doi:10.1126/sciadv.aay7193 · Cited by 69 · see citing works
Disorders of synaptic vesicle fusion machinery
Melland, H., Arvell, E. H., & Gordon, S. L. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15181 · Cited by 65 · see citing works
“Debate has long raged regarding the ability of complexin to clamp spontaneous release (for example, see reviews Rizo, 2018; Trimbuch & Rosenmund, 2016)), and differences likely arise from the model system used.”
BackgroundInfluentialSNARE Regulatory Proteins in Synaptic Vesicle Fusion and Recycling
Sauvola, C. W., & Littleton, J. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.733138 · Cited by 53 · see citing works
“Two competing models for the order of SNARE incorporation into the SNARE complex have been described (Rizo, 2018).”
BackgroundMethodCASK modulates the assembly and function of the Mint1/Munc18-1 complex to regulate insulin secretion
Zhang, Z., Li, W., Yang, G., Lü, X., Qi, X., Wang, S., Cao, C., Zhang, P., Ren, J., Zhao, J., et al. (2020) · Cell Discovery · doi:10.1038/s41421-020-00216-3 · Cited by 66 · see citing works
Grushin, K., Kalyana Sundaram, R. V., Sindelar, C. V., & Rothman, J. E. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2121259119 · Cited by 66 · see citing works
“More generally, it has long been appreciated that some sort of tilted/slanted state is needed sterically to enable SNARE assembly (21).”
BackgroundReal-time in vivo detection techniques for neurotransmitters: a review
Su, Y., Bian, S., & Sawan, M. (2020) · The Analyst · doi:10.1039/d0an01175d · Cited by 65 · see citing works
Morrison‐Levy, N., Borlot, F., Jain, P., & Whitney, R. (2020) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2020.12.001 · Cited by 64 · see citing works
Symmetrical arrangement of proteins under release-ready vesicles in presynaptic terminals
Radhakrishnan, A., Li, X., Grushin, K. S., Krishnakumar, S. S., Liu, J., & Rothman, J. E. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2024029118 · Cited by 64 · see citing works
“Based on the available structural and functional data, we believe that these tethering densities likely correspond to known SV tethering factors, like RIM1α and Munc13 (1, 14, 38) but cannot be conclusive at the present resolution.”
InfluentialSynaptophysin‐dependent synaptobrevin‐2 trafficking at the presynapse‐Mechanism and function
Cousin, M. A. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15499 · Cited by 64 · see citing works
“…release via its SNARE motif, which progressively interacts with the respective SNARE motifs of the plasma membrane target- SNAREs proteins syntaxin- 1 and synaptosomalassociated protein, 25 kDa (SNAP- 25) to drive SV fusion with the plasma membrane (Brunger et al., 2018; Rizo, 2018).”
BackgroundLong‐Term Safety and Clinical Effects of Nilotinib in Parkinson's Disease
Pagán, F., Wilmarth, B., Torres-Yaghi, Y. A., Hebron, M. L., Mulki, S., Ferrante, D., Matar, S., Ahn, J., & Moussa, C. (2020) · Movement Disorders · doi:10.1002/mds.28389 · Cited by 61 · see citing works
The neuronal calcium sensor Synaptotagmin-1 and SNARE proteins cooperate to dilate fusion pores
Wu, Z., Dharan, N., McDargh, Z. A., Thiyagarajan, S., O’Shaughnessy, B., & Karatekin, E. (2021) · eLife · doi:10.7554/elife.68215 · Cited by 58 · see citing works
Munc18-1 is crucial to overcome the inhibition of synaptic vesicle fusion by αSNAP
Stepien, K. P., Prinslow, E. A., & Rizo, J. (2019) · Nature Communications · doi:10.1038/s41467-019-12188-4 · Cited by 58 · see citing works
Self-citationSynaptic Vesicle Recycling and the Endolysosomal System: A Reappraisal of Form and Function
Ivanova, D., & Cousin, M. A. (2022) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2022.826098 · Cited by 56 · see citing works
“These include a physical attachment to the plasma membrane (docking), a transition to fusion competency (priming), and calcium-triggered fusion (exocytosis) (Brunger et al., 2018; Rizo, 2018).”
BackgroundMunc13- and SNAP25-dependent molecular bridges play a key role in synaptic vesicle priming
Papantoniou, C., Laugks, U., Betzin, J., Capitanio, C., Ferrero, J. J., Sánchez‐Prieto, J., Schoch, S., Brose, N., Baumeister, W. P., Cooper, B. H., et al. (2023) · Science Advances · doi:10.1126/sciadv.adf6222 · Cited by 55 · see citing works
“4A) and the MUN domain is homologous to tethering factors in other systems, Munc13 was hypothesized to form tethers ( 4 , 65 , 66 ).”
BackgroundResultInfluentialStructural basis for the clamping and Ca2+ activation of SNARE-mediated fusion by synaptotagmin
Grushin, K. S., Wang, J., Coleman, J., Rothman, J. E., Sindelar, C. V., & Krishnakumar, S. S. (2019) · Nature Communications · doi:10.1038/s41467-019-10391-x · Cited by 55 · see citing works
Synergistic roles of Synaptotagmin-1 and complexin in calcium-regulated neuronal exocytosis
Ramakrishnan, S. K., Bera, M., Coleman, J., Rothman, J. E., & Krishnakumar, S. S. (2020) · eLife · doi:10.7554/elife.54506 · Cited by 55 · see citing works
“The controlled yet rapid (sub-millisecond) release of neurotransmitters stored in synaptic vesicles (SVs) is central to all information processing in the brain (Südhof, 2013; Kaeser and Regehr, 2014; Rizo, 2018).”
BackgroundMethodInfluentialThe Role of α-Synuclein in SNARE-mediated Synaptic Vesicle Fusion
Yoo, G., Shin, Y., & Lee, N. K. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167775 · Cited by 52 · see citing works
In vivo Roles of Rab27 and Its Effectors in Exocytosis
Izumi, T. (2021) · Cell Structure and Function · doi:10.1247/csf.21043 · Cited by 52 · see citing works
“They are thought to com‐ mence fusion solely through stimulus-induced Ca 2+ binding to the C2 domain of synaptotagmin, which releases the con‐ straints imposed by the prefinal fusion complex consisting of SNAREs, synaptotagmin, and complexin (Brunger et al. , 2018; Rizo, 2018).”
BackgroundRizo, J., Sari, L., Qi, Y., Im, W., & Lin, M. M. (2022) · eLife · doi:10.7554/elife.76356 · Cited by 51 · see citing works
Self-citationRosikon, K. D., Bone, M. C., & Lawal, H. O. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.970405 · Cited by 52 · see citing works
“neurotransmitters to spill out into the synapse (Rizo, 2018).”
BackgroundInfluentialMichetti, C., Falace, A., Benfenati, F., & Fassio, A. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105856 · Cited by 52 · see citing works
“Recent reviews nicely and comprehensively update on the current knowledge on SV fusion and its Ca2+-dependent regulation (Brunger et al., 2019; Rizo, 2018; Sauvola and Littleton, 2021; Silva et al., 2021).”
BackgroundAldahabi, M., Balint, F., Holderith, N., Lorincz, A., Reva, M., & Nusser, Z. (2022) · Neuron · doi:10.1016/j.neuron.2022.09.035 · Cited by 50 · see citing works
“It is now generally accepted that Munc13 molecules are the master regulators of SV priming at central synapses (reviewed by Rizo, 2018).”
cAMP-Dependent Synaptic Plasticity at the Hippocampal Mossy Fiber Terminal
Shahoha, M., Cohen, R., Ben-Simon, Y., & Ashery, U. (2022) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2022.861215 · Cited by 46 · see citing works
“These includes the SNARE proteins, synaptotagmin, regulatory proteins, such as RAB3a, Munc13, Munc18, tomosyn, and active zone proteins, such as Piccolo, Bassoon and RIM1a, as well as several structural and endocytotic proteins (Dresbach et al., 2001; Südhof, 2013; Rizo, 2018; Chanaday et al., 2019).”
BackgroundDiscoidin Domain Receptor 1 is a therapeutic target for neurodegenerative diseases
Fowler, A. J., Hebron, M. L., Balaraman, K., Shi, W., Missner, A. A., Greenzaid, J. D., Chiu, T. L., Ullman, C. J., Weatherdon, E., Duka, V., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa177 · Cited by 47 · see citing works
“SNAP-25 gene expresses the trans-SNARE complex that mediates the fusion of synaptic vesicles with the plasma membrane, leading to neurotransmitter release (32).”
BackgroundLi, X., He, E., Chen, G., Cao, X., Zhao, L., Xu, X., Fu, Z., & Qiu, H. (2024) · Environment International · doi:10.1016/j.envint.2024.109026 · Cited by 42 · see citing works
Camacho, M., Quade, B., Trimbuch, T., Xu, J., Sari, L., Rizo, J., & Rosenmund, C. (2021) · eLife · doi:10.7554/elife.72030 · Cited by 42 · see citing works
“The sophisticated protein machinery that controls neurotransmitter release has been extensively characterized (Brunger et al., 2018; Rizo, 2018), yielding defined models for the functions of the central components of this machinery and allowing reconstitution of fundamental features of synaptic…”
BackgroundSelf-citationVardar, G., Salazar-Lázaro, A., Zobel, S., Trimbuch, T., & Rosenmund, C. (2022) · eLife · doi:10.7554/elife.78182 · Cited by 41 · see citing works
The function of VAMP2 in mediating membrane fusion: An overview
Yan, C., Jiang, J., Yang, Y., Geng, X., & Dong, W. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.948160 · Cited by 38 · see citing works
“SM proteins ensure the homology and specificity of SNARE pairing as well as vesicle fusion with the correct target membrane (De Haro et al., 2003; Shen et al., 2007; Xu et al., 2010; Ma et al., 2013; Baker et al., 2015; Rizo, 2018; Yu et al., 2018; Sauvola and Littleton, 2021).”
BackgroundS-Palmitoylation of Synaptic Proteins in Neuronal Plasticity in Normal and Pathological Brains
Buszka, A., Pytyś, A., Colvin, D., Włodarczyk, J., & Wójtowicz, T. (2023) · Cells · doi:10.3390/cells12030387 · Cited by 40 · see citing works
“Presynaptic vesicular release largely relies on the SNARE complex, formed by: synaptobrevin-2 (VAMP2), SNAP-25, and syntaxin1A or syntaxin-1B (STX1), assisted by modulatory synaptic proteins [184].”
Quercetin Attenuates Brain Oxidative Alterations Induced by Iron Oxide Nanoparticles in Rats
Dora, M. S., Taha, N., Lebda, M. A., Hashem, A. E., Elfeky, M., El-Sayed, Y. S., Jaouni, S. K. A., & El‐Far, A. H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22083829 · Cited by 40 · see citing works
“Neurotransmitters are endogenous chemical substances that allow neurons to communicate throughout the body; they enable the brain to perform different functions in the chemical synaptic transmission [40].”
BackgroundSTXBP1-associated neurodevelopmental disorder: a comparative study of behavioural characteristics
Study, T. D., O’Brien, S., Ng‐Cordell, E., Astle, D. E., Scerif, G., & Baker, K. (2019) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-019-9278-9 · Cited by 39 · see citing works
Proteomic Analysis of Mucopolysaccharidosis IIIB Mouse Brain
Pasquale, V. D., Costanzo, M., Siciliano, R. A., Mazzeo, M. F., Pistorio, V., Bianchi, L., Marchese, E., Ruoppolo, M., Pavone, L. M., & Caterino, M. (2020) · Biomolecules · doi:10.3390/biom10030355 · Cited by 37 · see citing works
“The brain membrane transport protein Stxbp1, also known as Munc18-1, is a key component of synaptic vesicle-fusion machinery, thus playing an important role in neurotransmitter secretion [73].”
BackgroundMéchaussier, S., Almoallem, B., Zeitz, C., Schil, K. V., Jeddawi, L., Dorpe, J. V., Rey, A. D., Condroyer, C., Pellé, O., Polak, M., et al. (2020) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2020.04.018 · Cited by 37 · see citing works
Energetics, kinetics, and pathways of SNARE assembly in membrane fusion
Zhang, Y., Ma, L., & Bao, H. (2022) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2022.2121804 · Cited by 34 · see citing works
“…regulate SNARE assembly, including NSF, SNAP, Munc13-1, synaptotagmin, and complexin, have recently been reviewed elsewhere (Baker and Hughson 2016; Brunger et al. 2018; Brunger et al. 2018; Rizo 2018; Brose et al. 2019; Brunger et al. 2019; Zhang and Hughson 2021; Koike and Jahn 2022; Rizo 2022).”
BackgroundSynaptotagmin-1–, Munc18-1–, and Munc13-1–dependent liposome fusion with a few neuronal SNAREs
Stepien, K. P., & Rizo, J. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2019314118 · Cited by 35 · see citing works
“Hence, synaptic vesicle fusion depends on a delicate balance between inhibitory and stimulatory interactions among the components of the release machinery, many of which perform both active and inhibitory roles (2).”
BackgroundInfluentialSelf-citationDynamin controls neuropeptide secretion by organizing dense-core vesicle fusion sites
Moro, A., van Nifterick, A. M., Toonen, R. F. G., & Verhage, M. (2021) · Science Advances · doi:10.1126/sciadv.abf0659 · Cited by 34 · see citing works
“The non-fusogenic cis-SNARE complexes and syntaxin tetramers can both be disassembled by SNAP/NSF [reviewed in (78, 79)].”
BackgroundThe neurotoxic effect of lactational PFOS exposure on cerebellar functional development in male mice
Ninomiya, A., Mshaty, A., Haijima, A., Yajima, H., Kokubo, M., Khairinisa, M. A., Ariyani, W., Fujiwara, Y., Ishii, S., Hosoi, N., et al. (2021) · Food and Chemical Toxicology · doi:10.1016/j.fct.2021.112751 · Cited by 35 · see citing works
Structural and mechanistic insights into secretagogin-mediated exocytosis
Qin, J., Liu, Q., Liu, Z., Pan, Y.-Z., Sifuentes-Dominguez, L., Stepien, K. P., Wang, Y., Tu, Y., Tan, S., Wang, Y., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1919698117 · Cited by 34 · see citing works
“Thus, Munc181 has been implicated in the correct transport of syntaxin-1 to the PM (44) and, although it is clear that Munc18-1 or Unc-18 plays crucial roles in neurotransmitter release beyond its syntaxin-1 chaperone function (13, 45), strong evidence indicates that Munc18-1 binding is critical to keep syntaxin-1 in…”
BackgroundSelf-citationAdvanced nano delivery system for stem cell therapy for Alzheimer's disease
Pan, Y., Li, L., Cao, N., Liao, J., Chen, H., & Zhang, M. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.122852 · Cited by 32 · see citing works
The Sec1/Munc18 protein Vps45 holds the Qa-SNARE Tlg2 in an open conformation
Eisemann, T., Allen, F., Lau, K., Shimamura, G. R., Jeffrey, P. D., & Hughson, F. M. (2020) · eLife · doi:10.7554/elife.60724 · Cited by 31 · see citing works
“The stringent regulation of neurotransmitter release requires the control of synaptic SNARE complex formation by Munc18, which clamps Stx in an inactive closed conformation, and Munc13-1, which mediates Stx opening (Brunger et al., 2018; Rizo, 2018).”
BackgroundRe‐examining how Munc13‐1 facilitates opening of syntaxin‐1
Magdziarek, M., Bolembach, A. A., Stepien, K. P., Quade, B., Liu, X., & Rizo, J. (2020) · Protein Science · doi:10.1002/pro.3844 · Cited by 30 · see citing works
“SNARE indicates the SNARE motif and N-pep indicates the N-peptide of syntaxin-1, which contributes to Munc18-1 binding.(2) Mutations used in this study are indicated below the syntaxin-1 diagram.”
MethodSelf-citationMorphofunctional changes at the active zone during synaptic vesicle exocytosis
Radecke, J., Seeger, R., Kádková, A., Laugks, U., Khosrozadeh, A., Goldie, K. N., Lučić, V., Sørensen, J. B., & Zuber, B. (2023) · EMBO Reports · doi:10.15252/embr.202255719 · Cited by 29 · see citing works
“These events include small SV fusion pore opening ( The notion that the SV fusion pore opening is the last step before the full SV collapse is well established, and it was hypothesized that lipid membrane perturbation and/or lipid point contact precede pore opening (Rizo, 2018).”
André, T., Classen, J., Brenner, P., Betts, M. J., Dörr, B., Kreye, S., Zuidinga, B., Meijer, M., Russell, R. B., Verhage, M., et al. (2020) · eNeuro · doi:10.1523/eneuro.0278-20.2020 · Cited by 28 · see citing works
Vesicular Release of GABA by Mammalian Horizontal Cells Mediates Inhibitory Output to Photoreceptors
Hirano, A. A., Vuong, H. E., Kornmann, H. L., Schietroma, C., Stella, S., Barnes, S., & Brecha, N. C. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.600777 · Cited by 28 · see citing works
“In the CNS, GAD65 is enriched in axonal terminals of GABAergic neurons (Esclapez et al., 1994).”
BackgroundInfluentialWu, X., Qiu, H., & Zhang, M. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167629 · Cited by 28 · see citing works
The Decade of Super-Resolution Microscopy of the Presynapse
Nosov, G., Kahms, M., & Klingauf, J. (2020) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2020.00032 · Cited by 26 · see citing works
“In this way, Munc13-1 provides platforms for open Syntaxin1A molecules to generate activated SNARE complexes (Rizo, 2018) that facilitate bridging of PM and SVs.”
BackgroundA unique C2 domain at the C terminus of Munc13 promotes synaptic vesicle priming
Padmanarayana, M., Liu, H., Michelassi, F. E., Li, L., Betensky, D. J., Dominguez, M. J., Sutton, R. B., Hu, Z., & Dittman, J. S. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2016276118 · Cited by 27 · see citing works
Synaptopathy: presynaptic convergence in frontotemporal dementia and amyotrophic lateral sclerosis
Clayton, E. L., Huggon, L., Cousin, M. A., & Mizielinska, S. (2024) · Brain · doi:10.1093/brain/awae074 · Cited by 25 · see citing works
“48,49 This release is highly synchronous and is mediated by the calcium-sensing synaptic vesicle protein synaptotagmin-1.”
BackgroundInfluentialDifferential nanoscale organization of excitatory synapses onto excitatory vs. inhibitory neurons
Dharmasri, P. A., Levy, A. D., & Blanpied, T. A. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2315379121 · Cited by 25 · see citing works
Microbiota Gut–Brain Axis and Autism Spectrum Disorder: Mechanisms and Therapeutic Perspectives
Petropoulos, A., Stavropoulou, E., Tsigalou, C., & Bezirtzoglou, E. (2025) · Nutrients · doi:10.3390/nu17182984 · Cited by 33 · see citing works
“It is notable that children with ASD, who have intrinsic neural atypicality, also manifest disordered gut–brain interactions [36].”
Function of Drosophila Synaptotagmins in membrane trafficking at synapses
Quiñones-Frías, M. C., & Littleton, J. T. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03788-9 · Cited by 23 · see citing works
Wu, S., Fan, J., Tang, F., Chen, L., Zhang, X., Xiao, D., & Li, X. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1123561 · Cited by 24 · see citing works
“Many molecules participate in the regulation of this process, including the SNARE complex, Munc18-1, and Ca2+ channels (Rizo, 2018).”
BackgroundInfluentialSynaptotagmin-1 and Doc2b Exhibit Distinct Membrane-Remodeling Mechanisms
Sorkin, R., Marchetti, M., Logtenberg, E., Piontek, M. C., Kerklingh, E., Brand, G., Voleti, R., Rizo, J., Roos, W. H., Groffen, A. J. A., et al. (2019) · Biophysical Journal · doi:10.1016/j.bpj.2019.12.021 · Cited by 23 · see citing works
Self-citationKulkarni, R., Kumari, S., Dhapola, R., Sharma, P., Singh, S. K., Medhi, B., & HariKrishnaReddy, D. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04545-2 · Cited by 23 · see citing works
“Neurotransmitters are chemical substances that provide links between neurons throughout the body via synapses [95].”
Molecular architecture of black widow spider neurotoxins
Chen, M., Blum, D. J., Engelhard, L., Raunser, S., Wagner, R., & Gatsogiannis, C. (2021) · Nature Communications · doi:10.1038/s41467-021-26562-8 · Cited by 22 · see citing works
Wei, Z., Wei, M., Yang, X., Xu, Y., Gao, S., & Ren, K. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/9176923 · Cited by 24 · see citing works
“Table 2: A list of neurotransmitter release processes [19].”
InfluentialOpen syntaxin overcomes exocytosis defects of diverse mutants in C. elegans
Tien, C.-W., Yu, B., Huang, M., Stepien, K. P., Sugita, K., Xie, X., Han, L., Monnier, P. P., Zhen, M., Rizo, J., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19178-x · Cited by 22 · see citing works
Self-citationWu, Z., Ma, L., Courtney, N. A., Zhu, J., Landajuela, A., Zhang, Y., Chapman, E. R., & Karatekin, E. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.1385-21.2022 · Cited by 21 · see citing works
The Nanoscopic Organization of Synapse Structures: A Common Basis for Cell Communication
Yang, X., & Annaert, W. G. (2021) · Membranes · doi:10.3390/membranes11040248 · Cited by 21 · see citing works
“The studies on the pre-synaptic compartment have mainly focused on the machinery responsible for neurotransmitter release from synaptic vesicles, including the cytomatrix active zone (CAZ) proteins, SNARE complexes, and voltage-gated calcium channels (VGCCs) [69,70].”
BackgroundKrejcar, O., & Namazi, H. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1537462 · Cited by 20 · see citing works
“Additionally, scientists provided quantitative insights into calcium-triggered neurotransmitter release, which plays a critical role in synaptic efficacy and homeostasis (Rizo, 2018).”
Han, B., Zhao, Y., Yao, J., Li, N., Fang, T., Wang, Y., Meng, Z., & Liu, W. (2022) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2022.115475 · Cited by 20 · see citing works
Shi, V., Craig, T. J., Bishop, P., Nakamura, Y., Rocca, D. L., Wilkinson, K. A., & Henley, J. M. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15161 · Cited by 20 · see citing works
“Stx-1 contains a single C-terminal transmembrane domain, a SNARE domain (known as H3) and an N-terminal regulatory domain that binds Munc-18-1 (Padmanabhan et al., 2019; Rizo, 2018).”
BackgroundSynaptophysin controls synaptobrevin-II retrieval via a cryptic C-terminal interaction site
Harper, C. B., Blumrich, E., & Cousin, M. A. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100266 · Cited by 19 · see citing works
“The SNARE complex is broken apart through the action of NSF (43, 44), before SybII is captured by Syp (10).”
BackgroundLytic granule exocytosis at immune synapses: lessons from neuronal synapses
Chang, H., Schirra, C., Pattu, V., Krause, E., & Becherer, U. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1177670 · Cited by 19 · see citing works
Complexin Membrane Interactions: Implications for Synapse Evolution and Function
Lottermoser, J. A., & Dittman, J. S. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167774 · Cited by 18 · see citing works
The beginning and the end of SNARE ‐induced membrane fusion
Mion, D., Bunel, L., Heo, P., & Pincet, F. (2022) · FEBS Open Bio · doi:10.1002/2211-5463.13447 · Cited by 17 · see citing works
Correia, D., Bellot, M., Prats, E., Gómez‐Canela, C., Moro, H., Raldúa, D., Domingues, I., Oliveira, M., & Faria, M. (2023) · Chemosphere · doi:10.1016/j.chemosphere.2023.140468 · Cited by 17 · see citing works
Peptide nucleic acids: Recent advancements and future opportunities in biomedical applications
Sannigrahi, A., De, N., Bhunia, D., & Bhadra, J. (2025) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2025.108146 · Cited by 17 · see citing works
Crummy, E., Mani, M., Thellman, J. C., & Martin, T. F. J. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.007504 · Cited by 17 · see citing works
“cells, SNARE complex formation prior to membrane fusion occurs in a vesicle priming step that requires the regulatory factors Munc18 –1, ubMunc13–2, and CAPS1 (25, 26).”
BackgroundGundersen, C. B. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101758 · Cited by 17 · see citing works
Non-ionotropic voltage-gated calcium channel signaling
Trus, M., & Atlas, D. (2024) · Channels · doi:10.1080/19336950.2024.2341077 · Cited by 16 · see citing works
Bhaskar, B. R., Yadav, L., Sriram, M., Sanghrajka, K., Gupta, M., Boby, K., V, Nellikka, R. K., & Das, D. (2024) · Nature Communications · doi:10.1038/s41467-024-46965-7 · Cited by 16 · see citing works
“A few crucial regulatory proteins believed to operate at this stage are synaptotagmin1, complexin, Munc13-1, and Munc18-1 22,24 .”
BackgroundNeurotransmitters responsible for purinergic motor neurotransmission and regulation of GI motility
Sanders, K. M., & Mutafova–Yambolieva, V. N. (2021) · Autonomic Neuroscience · doi:10.1016/j.autneu.2021.102829 · Cited by 16 · see citing works
Phosphoproteomic analysis of cocaine memory extinction and reconsolidation in the nucleus accumbens
Torregrossa, M. M., MacDonald, M. L., Stone, K. L., Lam, T. T., Nairn, A. C., & Taylor, J. R. (2018) · Psychopharmacology · doi:10.1007/s00213-018-5071-9 · Cited by 14 · see citing works
“The other phosphorylation event found to be upregulated after cue extinction in both the NAc and BLAwas on S14 of syntaxin 1a. Syntaxins are located presynaptically and are part of the SNARE complex that regulates vesicle exocytosis and neurotransmitter release (Rizo 2018).”
BackgroundYang, X., Tu, W., Gao, X., Zhang, Q., Guan, J., & Zhang, J. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1096365 · Cited by 13 · see citing works
“Munc18-1 complexed with Syntaxin-1 inhibits the production of Syntaxin-1 error SNARE complexes (34, 35).”
BackgroundEffects of Physical Cues on Stem Cell-Derived Extracellular Vesicles toward Neuropathy Applications
Berry, D., Ene, J., Nathani, A., Singh, M. S., Li, Y., & Zeng, C. (2024) · Biomedicines · doi:10.3390/biomedicines12030489 · Cited by 14 · see citing works
“The action potential depolarizes the cellular membrane to activate voltage-gated ion channels that release neurotransmitters via exocytosis [75,77,78].”
BackgroundHempel, T., Plattner, N., & Noé, F. (2020) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.0c00043 · Cited by 13 · see citing works
Actions of Rab27B‐GTPase on mammalian central excitatory synaptic transmission
Arias-Hervert, E. R., Xu, N., Njus, M. M., Murphy, G. G., Hou, Y.-N., Williams, J. A., Lentz, S., Ernst, S. A., & Stuenkel, E. (2020) · Physiological Reports · doi:10.14814/phy2.14428 · Cited by 14 · see citing works
“…of excitatory neurons the cycling in functional activity of SNARE proteins and Rab-GTPases, along with dynamic regulation by signaling elements, is central to the compartmentalized targeting and Ca2+-regulated exocytotic fusion of synaptic vesicles (SVs) (Binotti, Jahn, Chua, 2016; Rizo, 2018).”
Background
- Authors
- Rizo, J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Rizo, Josep
- ORCID
- Rizo, Josep
- Venue
- Protein Science
- Publisher
- Wiley
- Published
- 2018-07-10
- Volume
- 27
- Issue
- 8
- Pages
- 1364-1391
- ISSN
- 0961-8368 (ISSN-L)
- 1469-896X
- PMC
- PMC6153415
- OpenAlex
- W2941374900
- Cited by
- 210
- References
- 242
- Citations by year
- 2026: 19 · 2025: 16 · 2024: 18 · 2023: 24 · 2022: 37 · 2021: 36 · 2020: 34 · 2019: 23 · 2018: 3
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Protein Science (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Welch Foundation (I‐1304)
- NIH (R35‐NS097333)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- neurotransmitter release, synaptic vesicle exocytosis, SNARE complex, syntaxin-1, SNAP-25, synaptobrevin 2, NSF, Munc18-1, Munc13-1, synaptotagmin-1, complexin, calcium sensor, exocytosis regulation
- MeSH terms
- Animals, Humans, Membrane Fusion, Synaptic Transmission, Neurotransmitter Agents, SNARE Proteins, Mice
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