scholarly journals SNAREs and Synaptotagmin cooperatively determine the Ca2+ sensitivity of neurotransmitter release in fixed stoichiometry modules

2021 ◽  
Author(s):  
Zachary A McDargh ◽  
Ben A O'Shaughnessy
Keyword(s):  
Molecular Dynamics ◽  
Neurotransmitter Release ◽  
Release Site ◽  
Snare Complex ◽  
Snare Proteins ◽  
Stoichiometric Ratio ◽  
Release Rates ◽  
Vesicle Tethering ◽  
Fusion Site ◽  
Dynamics Simulations

Neurotransmitter release is accomplished by a multi-component machinery including the membrane-fusing SNARE proteins and Ca2+-sensing Synaptotagmin molecules. However, the Ca2+ sensitivity of release was found to increase or decrease with more or fewer SNARE complexes at the release site, respectively, while the cooperativity is unaffected (Acuna et al., 2014; Arancillo et al., 2013), suggesting that there is no simple division of labor between these two components. To examine the mechanisms underlying these findings, we developed molecular dynamics simulations of the neurotransmitter release machinery, with variable numbers of Synaptotagmin molecules and assembled SNARE complexes at the release site. Ca2+ uncaging simulations showed that increasing the number of SNARE complexes at fixed stoichiometric ratio of Synaptotagmin to SNAREs increased the Ca2+ sensitivity without affecting the cooperativity. The physiological cooperativity of ~4-5 was reproduced with 2-3 Synaptotagmin molecules per SNARE complex, suggesting that Synaptotagmin and SNAREs cooperate in fixed stoichiometry modules. In simulations of action potential-evoked release, increased numbers of Synaptotagmin-SNARE modules increased release probability, consistent with experiment. Our simulations suggest that the final membrane fusion step is driven by SNARE complex-mediated entropic forces, and by vesicle-tethering forces mediated by the long Synaptotagmin linker domains. In consequence, release rates are increased when more SNARE complexes and Synaptotagmin monomers are present at the fusion site.

scholarly journals Chemomechanical Regulation of SNARE Proteins Studied with Molecular Dynamics Simulations

2010 ◽  
Vol 99 (4) ◽  
pp. 1221-1230 ◽  
Author(s):  
Lars V. Bock ◽  
Brian Hutchings ◽  
Helmut Grubmüller ◽  
Dixon J. Woodbury
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Snare Proteins ◽  
Dynamics Simulations

scholarly journals Chemomechanical Regulation of Snare Proteins Studied with Molecular Dynamics Simulations

2010 ◽  
Vol 98 (3) ◽  
pp. 677a
Author(s):  
Lars Bock ◽  
Brian Hutchings ◽  
Helmut Grubmüller ◽  
Dixon J. Woodbury
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Snare Proteins ◽  
Dynamics Simulations

scholarly journals Complexin-1 regulated transition in the assembly of single neuronal SNARE complex

2021 ◽  
Author(s):  
Hao Tongrui ◽  
Feng Nan ◽  
Gong Fan ◽  
Liu Jiaquan ◽  
Lu Ma ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Molecular Mechanism ◽  
Optical Tweezers ◽  
Neurotransmitter Release ◽  
Snare Complex ◽  
Snare Proteins ◽  
Synaptic Vesicle Exocytosis ◽  
Sensitive Factor ◽  
Vesicle Exocytosis ◽  
Vesicle Pool

Neurotransmitter release is mediated by the synaptic vesicle exocytosis. Important proteins in this process have been identified including the molecular machine Synaptic-soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins, and other regulators. Complexin (Cpx) is one of the vital regulators in this process. The functions of Cpx are proposed to maintain a proper primed vesicle pool by preventing its premature depletion, which facilitates the vesicle fusion in the presence of Ca2+. However, the molecular mechanism remains unclear. Using dual-trap optical tweezers, we detected the interaction of complexin-1 (CpxI) with SNARE. We found that the CpxI stabilizes partially folded SNARE complexes by competing with C-terminal of Vamp protein and interacting with the C-terminal of t-SNARE complex.

scholarly journals PKA-catalyzed phosphorylation of tomosyn and its implication in Ca2+-dependent exocytosis of neurotransmitter

2005 ◽  
Vol 170 (7) ◽  
pp. 1113-1125 ◽  
Author(s):  
Takeshi Baba ◽  
Toshiaki Sakisaka ◽  
Sumiko Mochida ◽  
Yoshimi Takai
Keyword(s):  
Neurotransmitter Release ◽  
Regulatory Protein ◽  
Snare Complex ◽  
Snare Proteins ◽  
Dependent Protein Kinase ◽  
Readily Releasable Pool ◽  
Pituitary Adenylate Cyclase ◽  
Electrophysiological Studies ◽  
Cervical Ganglion ◽  
Dependent Protein

Neurotransmitter is released from nerve terminals by Ca2+-dependent exocytosis through many steps. SNARE proteins are key components at the priming and fusion steps, and the priming step is modulated by cAMP-dependent protein kinase (PKA), which causes synaptic plasticity. We show that the SNARE regulatory protein tomosyn is directly phosphorylated by PKA, which reduces its interaction with syntaxin-1 (a component of SNAREs) and enhances the formation of the SNARE complex. Electrophysiological studies using cultured superior cervical ganglion (SCG) neurons revealed that this enhanced formation of the SNARE complex by the PKA-catalyzed phosphorylation of tomosyn increased the fusion-competent readily releasable pool of synaptic vesicles and, thereby, enhanced neurotransmitter release. This mechanism was indeed involved in the facilitation of neurotransmitter release that was induced by a potent biological mediator, the pituitary adenylate cyclase-activating polypeptide, in SCG neurons. We describe the roles and modes of action of PKA and tomosyn in Ca2+-dependent neurotransmitter release.

scholarly journals All-atom molecular dynamics simulations of synaptic vesicle fusion I: a glimpse at the primed state

2021 ◽  
Author(s):  
Josep Rizo ◽  
Levent Sari ◽  
Yife Qi ◽  
Wonpil Im ◽  
Milo M Lin
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Plasma Membranes ◽  
Synaptotagmin 1 ◽  
Primed State ◽  
Dynamics Simulations ◽  
Synaptic Vesicle Fusion ◽  
Shed Light

Synaptic vesicles are primed into a state that is ready for fast neurotransmitter release upon Ca2+-binding to synaptotagmin-1. This state likely includes trans-SNARE complexes between the vesicle and plasma membranes that are bound to synaptotagmin-1 and complexins. However, the nature of this state and the steps leading to membrane fusion are unclear, in part because of the difficulty of studying this dynamic process experimentally. To shed light into these questions, we performed all-atom molecular dynamics simulations of systems containing trans-SNARE complexes between two flat bilayers or a vesicle and a flat bilayer with or without fragments of synaptotagmin-1 and/or complexin-1. Our results help visualize potential states of the release machinery en route to fusion, and suggest mechanistic features that may control the speed of release. In particular, the simulations suggest that the primed state contains almost fully assembled trans-SNARE complexes bound to the synaptotagmin-1 C2B domain and complexin-1 in a spring-loaded configuration where interactions of the C2B domain with the plasma membrane orient complexin-1 toward the vesicle, avoiding premature membrane merger but keeping the system ready for fast fusion upon Ca2+ influx.

scholarly journals Coupling of Ca2+-triggered unclamping and membrane fusion during neurotransmitter release

2021 ◽  
Author(s):  
Zachary A McDargh ◽  
Anirban Polley ◽  
Jin Zeng ◽  
Ben A O'Shaughnessy
Keyword(s):  
Power Law ◽  
Neurotransmitter Release ◽  
Plasma Membranes ◽  
Fusion Rate ◽  
Coarse Grained ◽  
Coupled Processes ◽  
Release Rates ◽  
Vesicle Release ◽  
Sequential Binding ◽  
Dynamics Simulations

Neurotransmitter (NT) release is accomplished by a machinery that unclamps fusion in response to calcium and then fuses the synaptic vesicle and plasma membranes. These are often thought of as distinct tasks assigned to non-overlapping components. Vesicle release rates have a power law dependence on [Ca2+] with an exponent of 3-5, long taken to indicate that 3-5 Ca2+ ions bind the calcium sensor Synaptotagmin to trigger release. However, dependencies at low [Ca2+] are inconsistent with simple sequential binding to a single Ca2+ sensor followed by a final fusion step. Here we developed coarse-grained molecular dynamics simulations of the NT release machinery accounting for Synaptotagmin-mediated unclamping and SNARE-mediated fusion. Calcium-triggered unclamping and SNARE-mediated fusion emerged from simulations as contemporaneous, coupled processes. Increasing cytosolic [Ca2+], the instantaneous fusion rate increased as SNAREpins were progressively and reversibly released by dissociation of Synaptotagmin-SNAREpin complexes. Simulations reproduced the observed dependence of release rates on [Ca2+], but the power law was unrelated to the number of Ca2+ ions required. Action potential-evoked vesicle release probabilities depended on the number of transiently unclamped SNAREpins, explaining experimental dependencies of release probabilities on both unclamping and membrane-fusing machinery components. These results describe a highly cooperative NT release machinery with intrinsically inseparable unclamping and membrane-fusing functionalities.

scholarly journals Insights into Membrane Fusion from Molecular Dynamics Simulations of SNARE Proteins

2012 ◽  
Vol 102 (3) ◽  
pp. 499a
Author(s):  
Alex Tek ◽  
Peter J. Bond ◽  
Mark S.P. Sansom ◽  
Marc Baaden
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Membrane Fusion ◽  
Snare Proteins ◽  
Dynamics Simulations

Molecular Dynamics Simulation of Fission Fragment Damage in Nuclear Fuel and Surrogate Material

MRS Advances ◽  
2017 ◽  
Vol 2 (21-22) ◽  
pp. 1225-1230 ◽  
Author(s):  
Ram Devanathan
Keyword(s):  
Molecular Dynamics ◽  
Nuclear Fuel ◽  
Unit Length ◽  
Heavy Ion ◽  
Dynamics Simulation ◽  
Stoichiometric Ratio ◽  
Damage State ◽  
Order Of Magnitude ◽  
Primary Damage ◽  
Dynamics Simulations

ABSTRACTWe have performed classical molecular dynamics simulations of swift heavy ion damage, typical of fission fragments, in nuclear fuel (UO2) for energy deposition per unit length of 3.9 keV/nm. We did not observe amorphization. The damage mainly consisted of isolated point defects. Only about 1% of the displacements occur on the uranium sublattice. Oxygen Frenkel pairs are an order of magnitude more numerous than uranium Frenkel pairs in the primary damage state. In contrast, previous results show that the ratio of Frenkel pairs on the two sublattices is close to the stoichiometric ratio in ceria. These differences in the primary damage state may lead to differences in radiation response of UO2 and CeO2.

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