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Nadezhda Sabeva, Richard W Cho, Alexander Vasin, Agustin Gonzalez, J Troy Littleton, Maria Bykhovskaia
: Synaptic vesicles fuse at morphological specializations in the presynaptic terminal termed active zones (AZs). Vesicle fusion can occur spontaneously or in response to an action potential. Following fusion, vesicles are retrieved and recycled within nerve terminals. It is still unclear whether vesicles that fuse spontaneously or following evoked release share similar recycling mechanisms. Genetic deletion of the SNARE-binding protein complexin dramatically increases spontaneous fusion, with the protein serving as the synaptic vesicle fusion clamp at Drosophila synapses...
December 2, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Melanie Schupp, Jörg Malsam, Marvin Ruiter, Andrea Scheutzow, Keimpe D B Wierda, Thomas H Söllner, Jakob B Sørensen
: Whether interactions between synaptotagmin-1 (syt-1) and the soluble NSF attachment protein receptors (SNAREs) are required during neurotransmission is debated. We examined five SNAP-25 mutations designed to interfere with syt-1 interactions. One mutation, D51/E52/E55A, targeted negative charges within region II of the primary interface (Zhou et al., 2015); two mutations targeted region I (D166A and D166/E170A) and one mutation targeted both (D51/E52/E55/D166A). The final mutation (D186/D193A) targeted C-terminal residues not expected to interact with syt-1...
November 23, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Alfredo Ramos-Miguel, Ken Sawada, Andrea A Jones, Allen E Thornton, Alasdair M Barr, Sue E Leurgans, Julie A Schneider, David A Bennett, William G Honer
Progressive accumulation of Alzheimer's disease-related pathology is associated with cognitive dysfunction. Differences in cognitive reserve may contribute to individual differences in cognitive function in the presence of comparable neuropathology. The protective effects of cognitive reserve could contribute differentially in early versus late stages of the disease. We investigated presynaptic proteins as measures of brain reserve (a subset of total cognitive reserve), and used Braak staging to estimate the progression of Alzheimer's disease...
November 19, 2016: Acta Neuropathologica
Jihong Gong, Ying Lai, Xiaohong Li, Mengxian Wang, Jeremy Leitz, Yachong Hu, Yunxiang Zhang, Ucheor B Choi, Daniel Cipriano, Richard A Pfuetzner, Thomas C Südhof, Xiaofei Yang, Axel T Brunger, Jiajie Diao
In presynaptic nerve terminals, complexin regulates spontaneous "mini" neurotransmitter release and activates Ca(2+)-triggered synchronized neurotransmitter release. We studied the role of the C-terminal domain of mammalian complexin in these processes using single-particle optical imaging and electrophysiology. The C-terminal domain is important for regulating spontaneous release in neuronal cultures and suppressing Ca(2+)-independent fusion in vitro, but it is not essential for evoked release in neuronal cultures and in vitro...
November 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
Alexander Vasin, Dina Volfson, J Troy Littleton, Maria Bykhovskaia
Neuronal transmitters are released from nerve terminals via the fusion of synaptic vesicles with the plasma membrane. Vesicles attach to membranes via a specialized protein machinery composed of membrane-attached (t-SNARE) and vesicle-attached (v-SNARE) proteins that zipper together to form a coiled-coil SNARE bundle that brings the two fusing membranes into close proximity. Neurotransmitter release may occur either in response to an action potential or through spontaneous fusion. A cytosolic protein, Complexin (Cpx), binds the SNARE complex and restricts spontaneous exocytosis by acting as a fusion clamp...
November 1, 2016: Biophysical Journal
Rebekah Elizabeth Mahoney, Jorge Azpurua, Benjamin A Eaton
Altered insulin signaling has been linked to widespread nervous system dysfunction including cognitive dysfunction, neuropathy and susceptibility to neurodegenerative disease. However, knowledge of the cellular mechanisms underlying the effects of insulin on neuronal function is incomplete. Here, we show that cell autonomous insulin signaling within the Drosophila CM9 motor neuron regulates the release of neurotransmitter via alteration of the synaptic vesicle fusion machinery. This effect of insulin utilizes the FOXO-dependent regulation of the thor gene, which encodes the Drosophila homologue of the eif-4e binding protein (4eBP)...
2016: ELife
Ying Lai, Ucheor B Choi, Yunxiang Zhang, Minglei Zhao, Richard A Pfuetzner, Austin L Wang, Jiajie Diao, Axel T Brunger
Complexin activates Ca(2+)-triggered neurotransmitter release and regulates spontaneous release in the presynaptic terminal by cooperating with the neuronal soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and the Ca(2+)-sensor synaptotagmin. The N-terminal domain of complexin is important for activation, but its molecular mechanism is still poorly understood. Here, we observed that a split pair of N-terminal and central domain fragments of complexin is sufficient to activate Ca(2+)-triggered release using a reconstituted single-vesicle fusion assay, suggesting that the N-terminal domain acts as an independent module within the synaptic fusion machinery...
August 9, 2016: Proceedings of the National Academy of Sciences of the United States of America
E R Mingazov, M V Ugrumov
It is assumed that one of the causes of the degeneration of dopaminergic neurons is the dysregulation of the vesicle cycle, which is ensured by a number of proteins including syntaxin I, synaptotagmin I, complexins I and II, and Rab5. It was shown that there is a compensatory increase in gene expression of proteins responsible for exocytosis at the preclinical stage of Parkinson's disease (PD) in the in substantia nigra (SN) in mice. Conversely, in the model of the clinical stage of PD, the decreases of gene expression of proteins responsible for exocytosis, endocytosis, and neuronal survival, which may be among the triggers of motor dysfunctions...
May 2016: Doklady. Biochemistry and Biophysics
Norbert Babai, Anna Sendelbeck, Hanna Regus-Leidig, Michaela Fuchs, Jasmin Mertins, Kerstin Reim, Nils Brose, Andreas Feigenspan, Johann Helmut Brandstätter
UNLABELLED: Complexins (Cplxs) are SNARE complex regulators controlling the speed and Ca(2+) sensitivity of SNARE-mediated synaptic vesicle fusion. We have shown previously that photoreceptor ribbon synapses in mouse retina are equipped with Cplx3 and Cplx4 and that lack of both Cplxs perturbs photoreceptor ribbon synaptic function; however, Cplx3/4 function in photoreceptor synaptic transmission remained elusive. To investigate Cplx3/4 function in photoreceptor ribbon synapses, voltage-clamp recordings from postsynaptic horizontal cells were performed in horizontal slice preparations of Cplx3/4 wild-type (WT) and Cplx3/4 double knock-out (DKO) mice...
June 22, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Ming Ying, Xiaojing Sui, Yanling Zhang, Qian Sun, Zhongsen Qu, Xiaobin Luo, Raymond Chuen-Chung Chang, Jiazuan Ni, Jianjun Liu, Xifei Yang
The molecular mechanisms underlying cognitive impairment in Alzheimer's disease (AD) remain largely unclear. In the present study, we were aimed to identify the potential key molecules involved in spatial memory impairment in a triple transgenic (3xTg-AD) mouse model of AD. By employing two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry, we revealed a total of 24 differentially expressed proteins in hippocampus of 9-month-old 3xTg-AD mice with significant spatial memory impairment in comparison to the age-matched controls...
June 22, 2016: Molecular Neurobiology
Jaewook Kim, Yicheng Zhu, Yeon-Kyun Shin
Complexin (Cpx) is a major regulator for Ca(2+)-triggered fast neuroexocytosis which underlies neuronal communication. Many psychiatric and neurological disorders accompany changes in the Cpx expression level, suggesting that abnormal Cpx levels may elicit aberrant cognitive symptoms. To comprehend how the changes in the Cpx level might affect neuronal communication, we investigated Ca(2+)-triggered exocytosis at various Cpx concentrations. Ca(2+)-triggered content-mixing between a single proteoliposome of t-SNARE and another single proteoliposome of v-SNARE plus Ca(2+)-sensor synaptotagmin 1 was examined with total internal reflection microscopy...
July 5, 2016: Biochemistry
Lena S Mortensen, Silvia J H Park, Jiang-Bin Ke, Benjamin H Cooper, Lei Zhang, Cordelia Imig, Siegrid Löwel, Kerstin Reim, Nils Brose, Jonathan B Demb, Jeong-Seop Rhee, Joshua H Singer
Complexin (Cplx) proteins modulate the core SNARE complex to regulate exocytosis. To understand the contributions of Cplx to signaling in a well-characterized neural circuit, we investigated how Cplx3, a retina-specific paralog, shapes transmission at rod bipolar (RB)→AII amacrine cell synapses in the mouse retina. Knockout of Cplx3 strongly attenuated fast, phasic Ca(2+)-dependent transmission, dependent on local [Ca(2+)] nanodomains, but enhanced slower Ca(2+)-dependent transmission, dependent on global intraterminal [Ca(2+)] ([Ca(2+)]I)...
June 7, 2016: Cell Reports
Linxiang Yin, Jaewook Kim, Yeon-Kyun Shin
Complexin (Cpx) is thought to be a major regulator of soluble N-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE)-dependent membrane fusion. Although the inhibition of membrane fusion by Cpx has been frequently reported, its structural basis has been elusive and an anticipated disruption of the SNARE core has never been observed. In the present study, to mimic the natural environment, we assembled a single SNAREpin between two nanodisc membrane patches. Single-molecule FRET (smFRET) detects a large conformational change, specifically at the C-terminal half, whereas no conformational change is observed at the N-terminal half...
July 15, 2016: Biochemical Journal
Dominique C Stephens, Hye Mi Kim, Arvind Kumar, Abdelbasset A Farahat, David W Boykin, Gregory M K Poon
Heterocyclic dications are receiving increasing attention as targeted inhibitors of transcription factors. While many dications act as purely competitive inhibitors, some fail to displace protein efficiently at drug concentrations expected to saturate their DNA target. To achieve a mechanistic understanding of these non-competitive effects, we used a combination of dications, which are intrinsically fluorescent and spectrally-separated fluorescently labeled DNA to dissect complex interactions in multi-component drug/DNA/protein systems...
May 19, 2016: Nucleic Acids Research
Satoshi Tadokoro, Naohide Hirashima, Naoko Utsunomiya-Tate
Mast cells are involved in allergic responses and undergo exocytotic release of inflammatory mediators in response to antigen stimulation. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins are involved in this membrane fusion process; some SNARE-binding proteins regulate SNARE-dependent liposome membrane fusion. SNARE-binding protein complexin II is expressed in mast cells, where it positively regulates exocytotic release after antigen stimulation. We found that complexin II suppressed SNARE-dependent membrane fusion between mast cell SNARE-containing liposomes...
2016: Biological & Pharmaceutical Bulletin
Ana María Cárdenas, Fernando D Marengo
The pattern of stimulation defines important characteristics of the secretory process in neurons and neuroendocrine cells, including the pool of secretory vesicles being recruited, the type and amount of transmitters released, the mode of membrane retrieval, and the mechanisms associated with vesicle replenishment. This review analyzes the mechanisms that regulate these processes in chromaffin cells, as well as in other neuroendocrine and neuronal models. A common factor in these mechanisms is the spatial and temporal distribution of the Ca(2+) signal generated during cell stimulation...
June 2016: Journal of Neurochemistry
Thorsten Trimbuch, Christian Rosenmund
When it comes to fusion with the neuronal cell membrane, does a synaptic vesicle have a choice whether to stop or to go? Recent work suggests that complexin, a tiny protein found within the synaptic terminal, contributes to the mechanism through which this choice is made. How complexin plays this consulting part and which synaptic vesicle proteins it interacts with remain open questions. Indeed, studies in mice and flies have led to the proposal of different models of complexin function. We suggest that understanding the modular nature of complexin will help us to unpick its role in synaptic vesicle release...
February 2016: Nature Reviews. Neuroscience
Laura J McMeekin, Elizabeth K Lucas, James H Meador-Woodruff, Robert E McCullumsmith, Robert C Hendrickson, Karen L Gamble, Rita M Cowell
The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) has been linked to multiple neurological and psychiatric disorders including schizophrenia, but its involvement in the pathophysiology of these disorders is unclear. Experiments in mice have revealed a set of developmentally-regulated cortical PGC-1α-dependent transcripts involved in calcium buffering (parvalbumin, PV), synchronous neurotransmitter release (synaptotagmin 2, Syt2; complexin 1, Cplx1) and axonal integrity (neurofilamaent heavy chain, Nefh)...
July 2016: Schizophrenia Bulletin
Xiaofei Yang, Jimin Pei, Yea Jin Kaeser-Woo, Taulant Bacaj, Nick V Grishin, Thomas C Südhof
Complexins are synaptic SNARE complex-binding proteins that cooperate with synaptotagmins in activating Ca(2+)-stimulated, synaptotagmin-dependent synaptic vesicle exocytosis and in clamping spontaneous, synaptotagmin-independent synaptic vesicle exocytosis. Here, we show that complexin sequences are conserved in some non-metazoan unicellular organisms and in all metazoans, suggesting that complexins are a universal feature of metazoans that predate metazoan evolution. We show that complexin from Nematostella vectensis, a cnidarian sea anemone far separated from mammals in metazoan evolution, functionally replaces mouse complexins in activating Ca(2+)-triggered exocytosis, but is unable to clamp spontaneous exocytosis...
October 2015: EMBO Reports
Ralf Mohrmann, Madhurima Dhara, Dieter Bruns
Despite intensive research, it is still unclear how an immediate and profound acceleration of exocytosis is triggered by appropriate Ca(2+)-stimuli in presynaptic terminals. This is due to the fact that the molecular mechanisms of "docking" and "priming" reactions, which set up secretory vesicles to fuse at millisecond time scale, are extremely hard to study. Yet, driven by a fruitful combination of in vitro and in vivo analyses, our mechanistic understanding of Ca(2+)-triggered vesicle fusion has certainly advanced in the past few years...
November 2015: Cellular and Molecular Life Sciences: CMLS
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