scholarly journals Protein–protein interactions and protein modules in the control of neurotransmitter release

1999 ◽  
Vol 354 (1381) ◽  
pp. 243-257 ◽  
Author(s):  
Fabio Benfenati ◽  
Franco Onofri ◽  
Silvia Giovedí
Keyword(s):  
Synaptic Vesicle ◽  
Protein Interactions ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Physiological Role ◽  
Presynaptic Membrane ◽  
Protein Protein Interactions ◽  
Sequence Of Events ◽  
Reserve Pool ◽  
Protein Modules

Information transfer among neurons is operated by neurotransmitters stored in synaptic vesicles and released to the extracellular space by an efficient process of regulated exocytosis. Synaptic vesicles are organized into two distinct functional pools, a large reserve pool in which vesicles are restrained by the actin–based cytoskeleton, and a quantitatively smaller releasable pool in which vesicles approach the presynaptic membrane and eventually fuse with it on stimulation. Both synaptic vesicle trafficking and neurotransmitter release depend on a precise sequence of events that include release from the reserve pool, targeting to the active zone, docking, priming, fusion and endocytotic retrieval of synaptic vesicles. These steps are mediated by a series of specific interactions among cytoskeletal, synaptic vesicle, presynaptic membrane and cytosolic proteins that, by acting in concert, promote the spatial and temporal regulation of the exocytotic machinery. The majority of these interactions are mediated by specific protein modules and domains that are found in many proteins and are involved in numerous intracellular processes. In this paper, the possible physiological role of these multiple protein–protein interactions is analysed, with ensuing updating and clarification of the present molecular model of the process of neurotransmitter release.

Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

2018 ◽  
Vol 25 (1) ◽  
pp. 5-21 ◽  
Author(s):  
Ylenia Cau ◽  
Daniela Valensin ◽  
Mattia Mori ◽  
Sara Draghi ◽  
Maurizio Botta
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Specific Protein ◽  
Protein Protein Interactions ◽  
Cellular Processes ◽  
Protein Partners ◽  
High Sequence Homology ◽  
Small Molecule Modulators

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

Recent Breakthroughs in Neurotransmitter Release: Paradigm for Regulated Exocytosis?

Physiology ◽  
1995 ◽  
Vol 10 (1) ◽  
pp. 42-46
Author(s):  
G Thiel
Keyword(s):  
Synaptic Vesicle ◽  
Brain Function ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Vesicle Trafficking ◽  
Regulated Exocytosis ◽  
Intracellular Vesicle ◽  
Vesicle Cycle ◽  
Synaptic Vesicle Cycle

Synaptic vesicles play a fundamental role in brain function by mediating the release of neurotransmitters. Neurons do not use an entirely unique secretion apparatus but rather a modification of the general secretion machinery. Moreover, the synaptic vesicle cycle has many similarities with intracellular vesicle trafficking pathways.

Neurotransmitter Release

2017 ◽  
Author(s):  
Peggy Mason
Keyword(s):  
Plasma Membrane ◽  
Synaptic Vesicle ◽  
Active Zone ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Synaptic Cleft ◽  
Fusion Pore ◽  
Synaptic Membrane ◽  
Specialized Region ◽  
Synaptic Vesicle Fusion

The biochemical and physiological processes of neurotransmitter release from an active zone, a specialized region of synaptic membrane, are examined. Synaptic vesicles containing neurotransmitters are docked at the active zone and then primed for release by SNARE complexes that bring them into extreme proximity to the plasma membrane. Entry of calcium ions through voltage-gated calcium channels triggers synaptic vesicle fusion with the synaptic terminal membrane and the consequent diffusion of neurotransmitter into the synaptic cleft. Release results when the fusion pore bridging the synaptic vesicle and plasma membrane widens and neurotransmitter from the inside of the synaptic vesicle diffuses into the synaptic cleft. Membrane from the active zone membrane is endocytosed, and synaptic vesicle proteins are then reassembled into recycled synaptic vesicles, allowing for more rounds of neurotransmitter release.

scholarly journals Botulinum Neurotoxin a Blocks Synaptic Vesicle Exocytosis but Not Endocytosis at the Nerve Terminal

1999 ◽  
Vol 147 (6) ◽  
pp. 1249-1260 ◽  
Author(s):  
Elaine A. Neale ◽  
Linda M. Bowers ◽  
Min Jia ◽  
Karen E. Bateman ◽  
Lura C. Williamson
Keyword(s):  
Synaptic Vesicle ◽  
Nerve Terminal ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Botulinum Neurotoxin ◽  
Vesicle Membrane ◽  
Botulinum Neurotoxin A ◽  
Synaptic Vesicle Exocytosis ◽  
Vesicle Exocytosis ◽  
Botulinum Neurotoxins

The supply of synaptic vesicles in the nerve terminal is maintained by a temporally linked balance of exo- and endocytosis. Tetanus and botulinum neurotoxins block neurotransmitter release by the enzymatic cleavage of proteins identified as critical for synaptic vesicle exocytosis. We show here that botulinum neurotoxin A is unique in that the toxin-induced block in exocytosis does not arrest vesicle membrane endocytosis. In the murine spinal cord, cell cultures exposed to botulinum neurotoxin A, neither K+-evoked neurotransmitter release nor synaptic currents can be detected, twice the ordinary number of synaptic vesicles are docked at the synaptic active zone, and its protein substrate is cleaved, which is similar to observations with tetanus and other botulinal neurotoxins. In marked contrast, K+ depolarization, in the presence of Ca2+, triggers the endocytosis of the vesicle membrane in botulinum neurotoxin A–blocked cultures as evidenced by FM1-43 staining of synaptic terminals and uptake of HRP into synaptic vesicles. These experiments are the first demonstration that botulinum neurotoxin A uncouples vesicle exo- from endocytosis, and provide evidence that Ca2+ is required for synaptic vesicle membrane retrieval.

scholarly journals A new life for an old pump: V-ATPase and neurotransmitter release

2014 ◽  
Vol 205 (1) ◽  
pp. 7-9 ◽  
Author(s):  
Stefano Vavassori ◽  
Andreas Mayer
Keyword(s):  
Plasma Membrane ◽  
Complex Formation ◽  
Membrane Fusion ◽  
Synaptic Vesicle ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Snare Complex ◽  
Spontaneous Release ◽  
Synaptic Vesicle Fusion ◽  
Snare Complex Formation

Neurons fire by releasing neurotransmitters via fusion of synaptic vesicles with the plasma membrane. Fusion can be evoked by an incoming signal from a preceding neuron or can occur spontaneously. Synaptic vesicle fusion requires the formation of trans complexes between SNAREs as well as Ca2+ ions. Wang et al. (2014. J. Cell Biol. http://dx.doi.org/jcb.201312109) now find that the Ca2+-binding protein Calmodulin promotes spontaneous release and SNARE complex formation via its interaction with the V0 sector of the V-ATPase.

scholarly journals Network-aware mutation clustering of cancer

2018 ◽  
Author(s):  
Swetansu Pattnaik ◽  
Catherine Vacher ◽  
Hong Ching Lee ◽  
Warren Kaplan ◽  
David M. Thomas ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Cancer Biology ◽  
Difficult Problem ◽  
The Cancer Genome Atlas ◽  
Precision Oncology ◽  
Protein Protein Interactions ◽  
Dna Mutation ◽  
Mutation Profile ◽  
Cancer Genome Atlas ◽  
Protein Modules

AbstractThe grouping of cancers across tissue boundaries is central to precision oncology, but remains a difficult problem. Here we present EPICC (Experimental Protein Interaction Clustering of Cancer), a novel technique to cluster cancer patients based on DNA mutation profile, that leverages knowledge of protein-protein interactions to reduce noise and amplify biological signal. We applied EPICC to data from The Cancer Genome Atlas (TCGA), and both recapitulated known cancer clusterings, and identified new cross-tissue cancer groups that may indicate novel cancer molecular subtypes. Investigation of EPICC clusters revealed new protein modules which were recurrently mutated across cancers, and indicate new avenues for research into cancer biology. EPICC leveraged the Vodafone DreamLab citizen science platform, and we provide our results as a resource for researchers to investigate the role of protein modules in cancer.

scholarly journals Synuclein Regulates Synaptic Vesicle Clustering and Docking at a Vertebrate Synapse

2021 ◽  
Vol 9 ◽  
Author(s):  
Kaitlyn E. Fouke ◽  
M. Elizabeth Wegman ◽  
Sarah A. Weber ◽  
Emily B. Brady ◽  
Cristina Román-Vendrell ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Active Zone ◽  
Synaptic Vesicles ◽  
Significant Loss ◽  
Binding Partner ◽  
Reserve Pool ◽  
Associated Proteins ◽  
Dose Dependent ◽  
Total Membrane ◽  
Synapsin 1

Neurotransmission relies critically on the exocytotic release of neurotransmitters from small synaptic vesicles (SVs) at the active zone. Therefore, it is essential for neurons to maintain an adequate pool of SVs clustered at synapses in order to sustain efficient neurotransmission. It is well established that the phosphoprotein synapsin 1 regulates SV clustering at synapses. Here, we demonstrate that synuclein, another SV-associated protein and synapsin binding partner, also modulates SV clustering at a vertebrate synapse. When acutely introduced to unstimulated lamprey reticulospinal synapses, a pan-synuclein antibody raised against the N-terminal domain of α-synuclein induced a significant loss of SVs at the synapse. Both docked SVs and the distal reserve pool of SVs were depleted, resulting in a loss of total membrane at synapses. In contrast, antibodies against two other abundant SV-associated proteins, synaptic vesicle glycoprotein 2 (SV2) and vesicle-associated membrane protein (VAMP/synaptobrevin), had no effect on the size or distribution of SV clusters. Synuclein perturbation caused a dose-dependent reduction in the number of SVs at synapses. Interestingly, the large SV clusters appeared to disperse into smaller SV clusters, as well as individual SVs. Thus, synuclein regulates clustering of SVs at resting synapses, as well as docking of SVs at the active zone. These findings reveal new roles for synuclein at the synapse and provide critical insights into diseases associated with α-synuclein dysfunction, such as Parkinson’s disease.

C-Cbl-PI3K Interaction Is Important for Platelet Outside-In Signaling

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2014-2014
Author(s):  
Claudia Lorena Buitrago ◽  
Satya P. Kunapuli ◽  
Archana Sanjay
Keyword(s):  
Actin Cytoskeleton ◽  
Protein Interactions ◽  
Conflicts Of Interest ◽  
Physiological Role ◽  
Human Platelets ◽  
Scaffolding Protein ◽  
Protein Protein Interactions ◽  
Clot Retraction ◽  
Knock Out

Abstract Abstract 2014 Platelet activation by outside-in signaling is initiated by the binding of fibrinogen to alphaIIbbeta3, an integrin only expressed in platelets and megakaryocytes. Signals transduced by alphaIIbbeta3 regulate actin cytoskeleton resulting in filopodia and lamellipodia formation, cell spreading and retraction. c-Cbl protein is abundantly expressed in platelets and functions as E3 ubiquitin ligase and scaffolding protein to mediate protein-protein interactions. Importantly, c-Cbl tyrosine 731 has been shown to interact with p85 subunit of phosphotidylinositol 3-kinase (PI3K) modulating the actin cytoskeleton. Although previous reports showed c-Cbl activation downstream of alphaIIbbeta3, the mechanisms and implications of this activation or the downstream targets remain to be elucidated. We have studied the role of c-Cbl in platelet outside-in signaling: Using human platelets we have demonstrated that c-Cbl Y700, Y731 and Y774 residues undergoes tyrosine phosphorylation upon platelet adhesion to immobilized fibrinogen. These phosphorylation events are completely inhibited in the presence of the pan Src Family Kinases (SFKs) inhibitor (PP2) suggesting that c-Cbl is phosphorylated downstream of SFKs. Spleen tyrosine kinase (Syk) is also involved in this signaling pathway since its inhibition significantly reduce c-Cbl phosphorylation at residues Y774 and Y700; interestingly, tyrosine 731 phosphorylation, which allows the interaction with the p85-subunit of PI3K, is not affected by Syk inhibition. The physiological role of c-Cbl in platelet outside-in signaling was studied using c-Cbl knock-out mice. We found that in contrast to WT platelets, c-Cbl KO platelets had a significantly reduced spreading over a fibrinogen-coated surface. Furthermore, clot retraction analysis demonstrated that c-Cbl KO platelets retraction time was delayed when compared to WT platelets, suggesting a retraction defect. To further elucidate the physiological role of c-Cbl-PI3K interaction we used a knock-in mouse in which the c-Cbl residue Y 731 was substituted with phenylalanine (Y731F) thereby abolishing the PI3K binding site on c-Cbl. Importantly, platelets from Y731F mice showed spreading and clot retraction defect that were comparable with the c-Cbl KO. These result indicates that in large part, the role of c-Cbl in platelets outside-in signaling is determined by its interaction with PI3K. In conclusion, we have demonstrated that c-Cbl plays an important role in platelet outside-in signaling, and its interaction with PI3K through tyrosine 731 is of pivotal importance in platelet spreading and retraction. Disclosures: No relevant conflicts of interest to declare.

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