Models of synaptotagmin‐1 to trigger Ca<sup>2+</sup>‐dependent vesicle fusion

Park, Yong Soo; Ryu, Je-Kyung

doi:10.1002/1873-3468.13193

Cited by 61 publications

(61 citation statements)

References 120 publications

(236 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A central assumption of our model is that activation of Syt1 by Ca 2+ binding lowers the fusion barrier ( Ruiter et al, 2019 ; Jackman and Regehr, 2017 ; Pérez-Lara et al, 2016 ; Park and Ryu, 2018 ). Several competing models have been proposed for this ( Park and Ryu, 2018 ). Both the Syt1 D232N mutant, where Ca 2+ -binding is mimicked, and the Syt1 4W mutant where hydrophobicity is increased, showed increased spontaneous and HS-induced release rates up to 250 mM HS, in line with a reduced fusion energy barrier.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Post-tetanic potentiation lowers the energy barrier for synaptic vesicle fusion independently of Synaptotagmin-1

Huson¹,

Meijer²,

Dekker³

et al. 2020

eLife

View full text Add to dashboard Cite

Previously, we showed that modulation of the energy barrier for synaptic vesicle fusion boosts release rates supralinearly (Schotten, 2015). Here we show that mouse hippocampal synapses employ this principle to trigger Ca2+-dependent vesicle release and post-tetanic potentiation (PTP). We assess energy barrier changes by fitting release kinetics in response to hypertonic sucrose. Mimicking activation of the C2A domain of the Ca2+-sensor Synaptotagmin-1 (Syt1), by adding a positive charge (Syt1D232N) or increasing its hydrophobicity (Syt14W), lowers the energy barrier. Removing Syt1 or impairing its release inhibitory function (Syt19Pro) increases spontaneous release without affecting the fusion barrier. Both phorbol esters and tetanic stimulation potentiate synaptic strength, and lower the energy barrier equally well in the presence and absence of Syt1. We propose a model where tetanic stimulation activates Syt1-independent mechanisms that lower the energy barrier and act additively with Syt1-dependent mechanisms to produce PTP by exerting multiplicative effects on release rates.

show abstract

Section: Discussionmentioning

confidence: 99%

“…A central assumption of our model is that activation of Syt1 by Ca 2+ binding lowers the fusion barrier [5,27,65,66]. Several competing models have been proposed for this [66].…”

Section: Activation Of Syt1's Ca 2+ Binding Domain Decreases the Fusimentioning

confidence: 99%

Post-tetanic potentiation lowers the energy barrier for synaptic vesicle fusion independently of Synaptotagmin-1

Huson¹,

Meijer²,

Dekker³

et al. 2020

eLife

View full text Add to dashboard Cite

show abstract

“… 156 It is a transmembrane protein anchored in the vesicle membranes containing 2 Ca 2+ -binding domains. In response to Ca 2+ -binding at elevated concentrations, synaptotagmin-1 triggers the vesicle fusion, but the exact molecular mechanisms remain to be elucidated (for review see Park and Ryu 157 ). Initial CSF studies of synaptotagmin-1 found it to be decreased in a CSF pool from patients with early-onset AD compared with a CSF pool from healthy controls.…”

Section: Fluid Biomarkers For Synapse Pathologymentioning

confidence: 99%

Fluid Biomarkers for Synaptic Dysfunction and Loss

et al. 2020

View full text Add to dashboard Cite

Synapses are the site for brain communication where information is transmitted between neurons and stored for memory formation. Synaptic degeneration is a global and early pathogenic event in neurodegenerative disorders with reduced levels of pre- and postsynaptic proteins being recognized as a core feature of Alzheimer’s disease (AD) pathophysiology. Together with AD, other neurodegenerative and neurodevelopmental disorders show altered synaptic homeostasis as an important pathogenic event, and due to that, they are commonly referred to as synaptopathies. The exact mechanisms of synapse dysfunction in the different diseases are not well understood and their study would help understanding the pathogenic role of synaptic degeneration, as well as differences and commonalities among them and highlight candidate synaptic biomarkers for specific disorders. The assessment of synaptic proteins in cerebrospinal fluid (CSF), which can reflect synaptic dysfunction in patients with cognitive disorders, is a keen area of interest. Substantial research efforts are now directed toward the investigation of CSF synaptic pathology to improve the diagnosis of neurodegenerative disorders at an early stage as well as to monitor clinical progression. In this review, we will first summarize the pathological events that lead to synapse loss and then discuss the available data on established (eg, neurogranin, SNAP-25, synaptotagmin-1, GAP-43, and α-syn) and emerging (eg, synaptic vesicle glycoprotein 2A and neuronal pentraxins) CSF biomarkers for synapse dysfunction, while highlighting possible utilities, disease specificity, and technical challenges for their detection.

show abstract

“…In the Rothman buttressed ring model , synaptotagmin‐1 oligomerizes into a ring with other components of the fusion machinery that rapidly dissociates upon calcium binding. In this Special Issue, Park and Ryu discuss the ring model, as well as other models of synaptotagmin‐1 function. Garcia‐Martinez et al .…”

mentioning

confidence: 99%

“…In the Rothman buttressed ring model [4], synaptotagmin-1 oligomerizes into a ring with other components of the fusion machinery that rapidly dissociates upon calcium binding. In this Special Issue, Park and Ryu [8] discuss the ring model, as well as other models of synaptotagmin-1 function. Garcia-Martinez et al [9] review lipids that modulate exocytosis through various mechanisms, including recruitment of fusion proteins to specific sites, modulation of local membrane properties or lipidation of key fusion proteins.…”

mentioning

confidence: 99%