Epileptic Phenotypes Associated With SNAREs and Related Synaptic Vesicle Exocytosis Machinery

SNAREs (soluble N-ethylmaleimide sensitive factor attachment protein receptor) are an heterogeneous family of proteins that, together with their key regulators, are implicated in synaptic vesicle exocytosis and synaptic transmission. SNAREs represent the core component of this protein complex. Although the specific mechanisms of the SNARE machinery is still not completely uncovered, studies in recent years have provided a clearer understanding of the interactions regulating the essential fusion machinery for neurotransmitter release. Mutations in genes encoding SNARE proteins or SNARE complex associated proteins have been associated with a variable spectrum of neurological conditions that have been recently defined as “SNAREopathies.” These include neurodevelopmental disorder, autism spectrum disorder (ASD), movement disorders, seizures and epileptiform abnormalities. The SNARE phenotypic spectrum associated with seizures ranges from simple febrile seizures and infantile spasms, to severe early-onset epileptic encephalopathies. Our study aims to review and delineate the epileptic phenotypes associated with dysregulation of synaptic vesicle exocytosis and transmission, focusing on the main proteins of the SNARE core complex (STX1B, VAMP2, SNAP25), tethering complex (STXBP1), and related downstream regulators.

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SNARE Complex Oligomerization by Synaphin/Complexin Is Essential for Synaptic Vesicle Exocytosis

Cell ◽

10.1016/s0092-8674(01)00229-x ◽

2001 ◽

Vol 104 (3) ◽

pp. 421-432 ◽

Cited By ~ 111

Author(s):

Hiroshi Tokumaru ◽

Keiko Umayahara ◽

Lorenzo L Pellegrini ◽

Toru Ishizuka ◽

Hideo Saisu ◽

...

Keyword(s):

Synaptic Vesicle ◽

Snare Complex ◽

Synaptic Vesicle Exocytosis ◽

Vesicle Exocytosis

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Sphingosine Facilitates SNARE Complex Assembly and Activates Synaptic Vesicle Exocytosis

Neuron ◽

10.1016/j.neuron.2009.04.024 ◽

2009 ◽

Vol 62 (5) ◽

pp. 683-694 ◽

Cited By ~ 100

Author(s):

Frédéric Darios ◽

Catherine Wasser ◽

Anastasia Shakirzyanova ◽

Artur Giniatullin ◽

Kerry Goodman ◽

...

Keyword(s):

Synaptic Vesicle ◽

Snare Complex ◽

Complex Assembly ◽

Synaptic Vesicle Exocytosis ◽

Vesicle Exocytosis

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Diverse modes of synaptic signaling, regulation, and plasticity distinguish two classes of C. elegans glutamatergic neurons

10.1101/175836 ◽

2017 ◽

Author(s):

Donovan Ventimiglia ◽

Cornelia I. Bargmann

Keyword(s):

Synaptic Vesicle ◽

Neuronal Cell ◽

Cell Types ◽

Snare Complex ◽

C Elegans ◽

Synaptic Vesicle Exocytosis ◽

High Calcium ◽

Vesicle Exocytosis ◽

Synaptic Dynamics

AbstractSynaptic vesicle release properties vary between neuronal cell types, but in most cases the molecular basis of this heterogeneity is unknown. Here, we compare in vivo synaptic properties of two neuronal classes in the C. elegans central nervous system, using VGLUT-pHluorin to monitor synaptic vesicle exocytosis and retrieval in intact animals. We show that the glutamatergic sensory neurons AWCON and ASH have distinct synaptic dynamics associated with tonic and phasic synaptic properties, respectively. Exocytosis in ASH and AWCON is differentially affected by SNARE-complex regulators that are present in both neurons: phasic ASH release is strongly dependent on UNC-13, whereas tonic AWCON release relies upon UNC-18 and on the protein kinase C homolog PKC-1. Exocytosis and retrieval each have two timescales in AWCON but one major timescale in ASH. Strong stimuli that elicit high calcium levels also increase exocytosis and retrieval rates in AWCON, generating distinct tonic and evoked synaptic modes. These results highlight the differential deployment of shared presynaptic proteins in neuronal cell type-specific functions.

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Differential inhibition by botulinum neurotoxin A of cotransmitters released from autonomic vasodilator neurons

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.281.5.h2124 ◽

2001 ◽

Vol 281 (5) ◽

pp. H2124-H2132 ◽

Cited By ~ 80

Author(s):

Judy L. Morris ◽

Phillip Jobling ◽

Ian L. Gibbins

Keyword(s):

Botulinum Neurotoxin ◽

Snare Complex ◽

Snare Proteins ◽

Botulinum Neurotoxin A ◽

Uterine Arteries ◽

Synaptic Vesicle Exocytosis ◽

Protein Receptor ◽

Autonomic Neurons ◽

Vesicle Exocytosis

The role of the soluble NSF attachment protein receptor (SNARE) protein complex in release of multiple cotransmitters from autonomic vasodilator neurons was examined in isolated segments of guinea pig uterine arteries treated with botulinum neurotoxin A (BoNTA; 50 nM). Western blotting of protein extracts from uterine arteries demonstrated partial cleavage of synaptosomal-associated protein of 25 kDa (SNAP-25) to a NH2-terminal fragment of ∼24 kDa by BoNTA. BoNTA reduced the amplitude (by 70–80%) of isometric contractions of arteries in response to repeated electrical stimulation of sympathetic axons at 1 or 10 Hz. The amplitude of neurogenic relaxations mediated by neuronal nitric oxide (NO) was not affected by BoNTA, whereas the duration of peptide-mediated neurogenic relaxations to stimulation at 10 Hz was reduced (67% reduction in integrated responses). In contrast, presynaptic cholinergic inhibition of neurogenic relaxations was abolished by BoNTA. These results demonstrate that the SNARE complex has differential involvement in release of cotransmitters from the same autonomic neurons: NO release is not dependant on synaptic vesicle exocytosis, acetylcholine release from small vesicles is highly dependant on the SNARE complex, and neuropeptide release from large vesicles involves SNARE proteins that may interact differently with regulatory factors such as calcium.

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

10.1101/2021.06.07.447331 ◽

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.

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Role of C2 domain proteins during synaptic vesicle exocytosis

Biochemical Society Transactions ◽

10.1042/bst0380213 ◽

2010 ◽

Vol 38 (1) ◽

pp. 213-216 ◽

Cited By ~ 21

Author(s):

Sascha Martens

Keyword(s):

Membrane Fusion ◽

Synaptic Vesicle ◽

Synaptic Vesicles ◽

Calcium Concentration ◽

Membrane Curvature ◽

Snare Complex ◽

C2 Domain ◽

C2 Domains ◽

Synaptic Vesicle Exocytosis ◽

Vesicle Exocytosis

Neurotransmitter release is mediated by the fusion of synaptic vesicles with the presynaptic plasma membrane. Fusion is triggered by a rise in the intracellular calcium concentration and is dependent on the neuronal SNARE (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor) complex. A plethora of molecules such as members of the MUNC13, MUNC18, complexin and synaptotagmin families act along with the SNARE complex to enable calcium-regulated synaptic vesicle exocytosis. The synaptotagmins are localized to synaptic vesicles by an N-terminal transmembrane domain and contain two cytoplasmic C2 domains. Members of the synaptotagmin family are thought to translate the rise in intracellular calcium concentration into synaptic vesicle fusion. The C2 domains of synaptotagmin-1 bind membranes in a calcium-dependent manner and in response induce a high degree of membrane curvature, which is required for its ability to trigger membrane fusion in vitro and in vivo. Furthermore, members of the soluble DOC2 (double-C2 domain) protein family have similar properties. Taken together, these results suggest that C2 domain proteins such as the synaptotagmins and DOC2s promote membrane fusion by the induction of membrane curvature in the vicinity of the SNARE complex. Given the widespread expression of C2 domain proteins in secretory cells, it is proposed that promotion of SNARE-dependent membrane fusion by the induction of membrane curvature is a widespread phenomenon.

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Diverse modes of synaptic signaling, regulation, and plasticity distinguish two classes of C. elegans glutamatergic neurons

eLife ◽

10.7554/elife.31234 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 6

Author(s):

Donovan Ventimiglia ◽

Cornelia I Bargmann

Keyword(s):

Synaptic Vesicle ◽

Neuronal Cell ◽

Cell Types ◽

Snare Complex ◽

C Elegans ◽

Synaptic Vesicle Exocytosis ◽

High Calcium ◽

Vesicle Exocytosis ◽

Synaptic Dynamics

Synaptic vesicle release properties vary between neuronal cell types, but in most cases the molecular basis of this heterogeneity is unknown. Here, we compare in vivo synaptic properties of two neuronal classes in the C. elegans central nervous system, using VGLUT-pHluorin to monitor synaptic vesicle exocytosis and retrieval in intact animals. We show that the glutamatergic sensory neurons AWCON and ASH have distinct synaptic dynamics associated with tonic and phasic synaptic properties, respectively. Exocytosis in ASH and AWCON is differentially affected by SNARE-complex regulators that are present in both neurons: phasic ASH release is strongly dependent on UNC-13, whereas tonic AWCON release relies upon UNC-18 and on the protein kinase C homolog PKC-1. Strong stimuli that elicit high calcium levels increase exocytosis and retrieval rates in AWCON, generating distinct tonic and evoked synaptic modes. These results highlight the differential deployment of shared presynaptic proteins in neuronal cell type-specific functions.

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Identification and characterization of Snapin as a ubiquitously expressed SNARE-binding protein that interacts with SNAP23 in non-neuronal cells

Biochemical Journal ◽

10.1042/bj20030427 ◽

2003 ◽

Vol 375 (2) ◽

pp. 433-440 ◽

Cited By ~ 59

Author(s):

Penelope BUXTON ◽

Xiang-Ming ZHANG ◽

Bong WALSH ◽

Absorn SRIRATANA ◽

Irina SCHENBERG ◽

...

Keyword(s):

Fusion Protein ◽

Fluorescent Protein ◽

Neuronal Cells ◽

Specific Protein ◽

Snare Complex ◽

Protein Fusion ◽

General Role ◽

Synaptic Vesicle Exocytosis ◽

Protein Receptor ◽

Vesicle Exocytosis

Members of the SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor) superfamily [syntaxins, VAMPs (vesicle-associated membrane proteins) and SNAP25 (synaptosome-associated protein-25)-related proteins] are required for intracellular membrane-fusion events in eukaryotes. In neurons, assembly of SNARE core complexes comprising the presynaptic membrane-associated SNAREs syntaxin 1 and SNAP25, and the vesicle-associated SNARE VAMP2, is necessary for synaptic vesicle exocytosis. Several accessory factors have been described that associate with the synaptic SNAREs and modulate core complex assembly or mediate Ca2+ regulation. One such factor, Snapin, has been reported to be a brain-specific protein that interacts with SNAP25, and regulates association of the putative Ca2+-sensor synaptotagmin with the synaptic SNARE complex [Ilardi, Mochida and Sheng (1999) Nat. Neurosci. 2, 119–124]. Here we demonstrate that Snapin is expressed ubiquitously in neuronal and non-neuronal cells. Furthermore, using protein–protein-interaction assays we show that Snapin interacts with SNAP23, the widely expressed homologue of SNAP25, and that the predicted C-terminal helical domain of Snapin contains the SNAP23-binding site. Subcellular localization experiments revealed that Snapin is a soluble protein that exists in both cytosolic and peripheral membrane-bound pools in adipocytes. Moreover, association of Snapin with the plasma membrane was detected in cells overexpressing a Snapin–green fluorescent protein fusion protein. Finally, we show that Snapin is able to form a ternary complex with SNAP23 and syntaxin 4, suggesting that it is a component of non-neuronal SNARE complexes. An important implication of our results is that Snapin is likely to perform a general role in SNARE-mediated vesicle fusion events in non-neuronal cells in addition to its participation in Ca2+-regulated neurosecretion.

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