scholarly journals Myosin V Regulates Spatial Localization of Different Forms of Neurotransmitter Release in Central Synapses

2021 ◽  
Vol 13 ◽  
Author(s):  
Dario Maschi ◽  
Michael W. Gramlich ◽  
Vitaly A. Klyachko
Keyword(s):  
Molecular Motor ◽  
Release Site ◽  
Dependent Manner ◽  
Myosin V ◽  
Spatiotemporal Organization ◽  
Spatial Shift ◽  
Spatially Distributed ◽  
Preferential Location ◽  
Central Synapses ◽  
Activity Dependent

Synaptic active zone (AZ) contains multiple specialized release sites for vesicle fusion. The utilization of release sites is regulated to determine spatiotemporal organization of the two main forms of synchronous release, uni-vesicular (UVR) and multi-vesicular (MVR). We previously found that the vesicle-associated molecular motor myosin V regulates temporal utilization of release sites by controlling vesicle anchoring at release sites in an activity-dependent manner. Here we show that acute inhibition of myosin V shifts preferential location of vesicle docking away from AZ center toward periphery, and results in a corresponding spatial shift in utilization of release sites during UVR. Similarly, inhibition of myosin V also reduces preferential utilization of central release sites during MVR, leading to more spatially distributed and temporally uniform MVR that occurs farther away from the AZ center. Using a modeling approach, we provide a conceptual framework that unites spatial and temporal functions of myosin V in vesicle release by controlling the gradient of release site release probability across the AZ, which in turn determines the spatiotemporal organization of both UVR and MVR. Thus myosin V regulates both temporal and spatial utilization of release sites during two main forms of synchronous release.

scholarly journals Myosin V regulates spatial localization of different forms of neurotransmitter release in central synapses

2020 ◽  
Author(s):  
Dario Maschi ◽  
Michael W. Gramlich ◽  
Vitaly A. Klyachko
Keyword(s):  
Neurotransmitter Release ◽  
Molecular Motor ◽  
Spatial Localization ◽  
Myosin V ◽  
Vesicle Docking ◽  
Spatial Shift ◽  
Spatially Distributed ◽  
Temporal And Spatial ◽  
Preferential Location ◽  
Central Synapses

SUMMARYSynaptic active zone (AZ) contains multiple specialized release sites for vesicle fusion. The utilization of release sites is regulated to determine spatiotemporal organization of the two main forms of synchronous release, uni-vesicluar (UVR) and multi-vesicular (MVR). We previously found that the vesicle-associated molecular motor myosin V regulates temporal utilization of release sites by controlling vesicle anchoring at release sites (Maschi et al, 2018). Here we show that acute inhibition of myosin V shifts preferential location of vesicle docking away from AZ center towards periphery, and results in a corresponding spatial shift in utilization of release sites during UVR. Similarly, inhibition of myosin V also reduces preferential utilization of central release sites during MVR, leading to more spatially distributed and temporally uniform MVR that occurs farther away from the AZ center. Thus myosin V regulates both temporal and spatial utilization of release sites during two main forms of synchronous release.

scholarly journals An activity-dependent local transport regulation via degradation and synthesis of KIF17 underlying cognitive flexibility

2020 ◽  
Vol 6 (51) ◽  
pp. eabc8355
Author(s):  
Suguru Iwata ◽  
Momo Morikawa ◽  
Yosuke Takei ◽  
Nobutaka Hirokawa
Keyword(s):  
Cognitive Flexibility ◽  
Molecular Motor ◽  
Fear Memory ◽  
Dependent Manner ◽  
Weight Changes ◽  
Regulatory Processes ◽  
Aspartate Receptor ◽  
Local Transport ◽  
Activity Dependent ◽  
Specific Deletion

Synaptic weight changes among postsynaptic densities within a single dendrite are regulated by the balance between localized protein degradation and synthesis. However, the molecular mechanism via these opposing regulatory processes is still elusive. Here, we showed that the molecular motor KIF17 was locally degraded and synthesized in an N-methyl-d-aspartate receptor (NMDAR)–mediated activity–dependent manner. Accompanied by the degradation of KIF17, its transport was temporarily dampened in dendrites. We also observed that activity-dependent local KIF17 synthesis driven by its 3′ untranslated region (3′UTR) occurred at dendritic shafts, and the newly synthesized KIF17 moved along the dendrites. Furthermore, hippocampus-specific deletion of Kif17 3′UTR disrupted KIF17 synthesis induced by fear memory retrieval, leading to impairment in extinction of fear memory. These results indicate that the regulation of the KIF17 transport is driven by the single dendrite–restricted cycle of degradation and synthesis that underlies cognitive flexibility.

scholarly journals Activity-regulated synaptic targeting of lncRNA ADEPTR mediates structural plasticity by localizing Sptn1 and AnkB in dendrites

2021 ◽  
Vol 7 (16) ◽  
pp. eabf0605
Author(s):  
Eddie Grinman ◽  
Yoshihisa Nakahata ◽  
Yosef Avchalumov ◽  
Isabel Espadas ◽  
Supriya Swarnkar ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Noncoding Rna ◽  
Molecular Motor ◽  
Structural Plasticity ◽  
Dependent Manner ◽  
Protein Coding ◽  
Synaptic Targeting ◽  
Conserved Sequence ◽  
Activity Dependent

Activity-dependent structural plasticity at the synapse requires specific changes in the neuronal transcriptome. While much is known about the role of coding elements in this process, the role of the long noncoding transcriptome remains elusive. Here, we report the discovery of an intronic long noncoding RNA (lncRNA)—termed ADEPTR—that is up-regulated and synaptically transported in a cAMP/PKA-dependent manner in hippocampal neurons, independently of its protein-coding host gene. Loss of ADEPTR function suppresses activity-dependent changes in synaptic transmission and structural plasticity of dendritic spines. Mechanistically, dendritic localization of ADEPTR is mediated by molecular motor protein Kif2A. ADEPTR physically binds to actin-scaffolding regulators ankyrin (AnkB) and spectrin (Sptn1) via a conserved sequence and is required for their dendritic localization. Together, this study demonstrates how activity-dependent synaptic targeting of an lncRNA mediates structural plasticity at the synapse.

scholarly journals A cAMP/PKA-dependent synaptically targeted lncRNA mediates structural plasticity in hippocampal neurons by functionally interacting with the Spectrin/Ankyrin Network

2020 ◽  
Author(s):  
Eddie Grinman ◽  
Yoshihisa Nakahata ◽  
Yosef Avchalumov ◽  
Isabel Espadas ◽  
Supriya Swarnkar ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Long Noncoding Rna ◽  
Hippocampal Neurons ◽  
Noncoding Rna ◽  
Molecular Motor ◽  
Structural Plasticity ◽  
Dependent Manner ◽  
Protein Coding ◽  
Activity Dependent

AbstractActivity-dependent structural plasticity at the synapse requires specific changes in the neuronal transcriptome. While much is known about the role of coding elements in this process, the role of the long-noncoding transcriptome remains elusive. Here we report the discovery of an intronic long noncoding RNA (lncRNA)—termed ADEPTR—whose expression is upregulated and is synaptically transported in a cAMP/PKA-dependent manner in hippocampal neurons, independent of its protein-coding host gene. Loss of ADEPTR function suppresses activity-dependent changes in synaptic transmission and structural plasticity of dendritic spines. Mechanistically, dendritic localization of ADEPTR is mediated by molecular motor protein Kif2A. ADEPTR physically binds to actin-scaffolding regulators Ankyrin (AnkB) and Spectrin (Sptn1) and is required for their dendritic localization. Taken together, this study demonstrates that ADEPTR regulates the dendritic Spectrin-Ankyrin network for structural plasticity at the synapse and illuminates a novel role for lncRNAs at the synapse.One Sentence SummaryWe have uncovered an intronic long noncoding RNA that is synaptically transported in a cAMP-dependent manner and is linked to cytoskeletal components of structural plasticity in hippocampal neurons.

scholarly journals Myosin V functions as a vesicle tether at the plasma membrane to control neurotransmitter release in central synapses

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Dario Maschi ◽  
Michael W Gramlich ◽  
Vitaly A Klyachko
Keyword(s):  
Plasma Membrane ◽  
Neurotransmitter Release ◽  
Repetitive Stimulation ◽  
Dependent Manner ◽  
Myosin V ◽  
Hippocampal Synapses ◽  
Vesicle Exocytosis ◽  
Central Synapses ◽  
Synaptic Vesicle Fusion ◽  
Single Vesicle

Synaptic vesicle fusion occurs at specialized release sites at the active zone. How refilling of release sites with new vesicles is regulated in central synapses remains poorly understood. Using nanoscale-resolution detection of individual release events in rat hippocampal synapses we found that inhibition of myosin V, the predominant vesicle-associated motor, strongly reduced refilling of the release sites during repetitive stimulation. Single-vesicle tracking revealed that recycling vesicles continuously shuttle between a plasma membrane pool and an inner pool. Vesicle retention at the membrane pool was regulated by neural activity in a myosin V dependent manner. Ultrastructural measurements of vesicle occupancy at the plasma membrane together with analyses of single-vesicle trajectories during vesicle shuttling between the pools suggest that myosin V acts as a vesicle tether at the plasma membrane, rather than a motor transporting vesicles to the release sites, or directly regulating vesicle exocytosis.

Extracellular Release of ILEI/FAM3C and Amyloid-β Is Associated with the Activation of Distinct Synapse Subpopulations

2021 ◽  
pp. 1-16
Author(s):  
Masaki Nakano ◽  
Yachiyo Mitsuishi ◽  
Lei Liu ◽  
Naoki Watanabe ◽  
Emi Hibino ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Epithelial Mesenchymal Transition ◽  
Surrogate Marker ◽  
Amyloid Β ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Extracellular Release ◽  
Activity Dependent ◽  
Aβ Production

Background: Brain amyloid-β (Aβ) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and Aβ deposition in Alzheimer’s disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for Aβ generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous Aβ suppressor. Objective: This study aimed to access the mechanism underlying ILEI secretion and its effect on Aβ production in the brain. Methods: ILEI and Aβ levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis in mutant human Aβ precursor protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA. Results: Extracellular release of ILEI and Aβ was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and Aβ revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of Aβ levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and Aβ levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of Aβ and were reduced in AD and mild cognitive impairment. Conclusion: ILEI and Aβ are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates Aβ production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain Aβ.

scholarly journals Molecular mechanisms for microtubule length regulation by kinesin-8 and XMAP215 proteins

2014 ◽  
Vol 4 (6) ◽  
pp. 20140031 ◽  
Author(s):  
Louis Reese ◽  
Anna Melbinger ◽  
Erwin Frey
Keyword(s):  
Molecular Motors ◽  
Molecular Mechanisms ◽  
Molecular Motor ◽  
Mutual Exclusion ◽  
High Growth ◽  
Dependent Manner ◽  
Dynamic Regulation ◽  
Filament Dynamics ◽  
Length Regulation ◽  
The Stability

The cytoskeleton is regulated by a plethora of enzymes that influence the stability and dynamics of cytoskeletal filaments. How microtubules (MTs) are controlled is of particular importance for mitosis, during which dynamic MTs are responsible for proper segregation of chromosomes. Molecular motors of the kinesin-8 protein family have been shown to depolymerize MTs in a length-dependent manner, and recent experimental and theoretical evidence suggests a possible role for kinesin-8 in the dynamic regulation of MTs. However, so far the detailed molecular mechanisms of how these molecular motors interact with the growing MT tip remain elusive. Here we show that two distinct scenarios for the interactions of kinesin-8 with the MT tip lead to qualitatively different MT dynamics, including accurate length control as well as intermittent dynamics. We give a comprehensive analysis of the regimes where length regulation is possible and characterize how the stationary length depends on the biochemical rates and the bulk concentrations of the various proteins. For a neutral scenario, where MTs grow irrespective of whether the MT tip is occupied by a molecular motor, length regulation is possible only for a narrow range of biochemical rates, and, in particular, limited to small polymerization rates. By contrast, for an inhibition scenario, where the presence of a motor at the MT tip inhibits MT growth, the regime where length regulation is possible is extremely broad and includes high growth rates. These results also apply to situations where a polymerizing enzyme like XMAP215 and kinesin-8 mutually exclude each other from the MT tip. Moreover, we characterize the differences in the stochastic length dynamics between the two scenarios. While for the neutral scenario length is tightly controlled, length dynamics is intermittent for the inhibition scenario and exhibits extended periods of MT growth and shrinkage. On a broader perspective, the set of models established in this work quite generally suggest that mutual exclusion of molecules at the ends of cytoskeletal filaments is an important factor for filament dynamics and regulation.

scholarly journals Epicutaneous Administration of Papain Induces IgE and IgG Responses in a Cysteine Protease Activity-Dependent Manner

2014 ◽  
Vol 63 (2) ◽  
pp. 219-226 ◽  
Author(s):  
Hideo Iida ◽  
Toshiro Takai ◽  
Yusuke Hirasawa ◽  
Seiji Kamijo ◽  
Sakiko Shimura ◽  
...  
Keyword(s):  
Cysteine Protease ◽  
Protease Activity ◽  
Dependent Manner ◽  
Cysteine Protease Activity ◽  
Activity Dependent

Evidence That Post-Tetanic Potentiation Is Mediated by Neuropeptide Release in Aplysia

2001 ◽  
Vol 86 (6) ◽  
pp. 2845-2855 ◽  
Author(s):  
Lyle E. Fox ◽  
Philip E. Lloyd
Keyword(s):  
Motor Neurons ◽  
High Frequency ◽  
Tetanic Stimulation ◽  
Neuropeptide Release ◽  
Neuromuscular Synapses ◽  
Excitatory Junction Potentials ◽  
Post Tetanic Potentiation ◽  
Central Synapses ◽  
Activity Dependent ◽  
Frequency Of Stimulation

Many neuromuscular and central synapses exhibit activity-dependent plasticity. The sustained high-frequency firing needed to elicit some forms of plasticity are similar to those often required to release neuropeptides. We wanted to determine if neuropeptide release could contribute to post-tetanic potentiation (PTP) and chose neuromuscular synapses in buccal muscle I3a to explore this issue. This muscle is innervated by two motor neurons (termed B3 and B38) that show PTP in response to tetanic stimulation. B3 and B38 use glutamate as their fast transmitter but express different modulatory neuropeptides. B3 expresses FMRFamide, a neuropeptide that only slightly increases its own excitatory junction potentials (EJPs). B38 expresses the small cardioactive peptide (SCP), a neuropeptide that dramatically increases its own EJPs. It was our hypothesis that SCP released from B38's terminals during tetanic stimulation mediated a component of PTP for B38. Because no antagonist to SCP currently exists, we used several indirect approaches to test this hypothesis. First, we studied the effects of increasing stimulation frequency during the tetanus or lowering temperature on PTP. Both of these changes are known to dramatically increase SCP release. We found that increasing the frequency of stimulation increased PTP for both neurons; however, the effects were larger for B38. Decreasing the temperature tended to reduce PTP for B3, while increasing PTP for B38. These results were consistent with known properties of SCP release from B38. Next we selectively superfused the neuromuscular synapses with exogenous SCP to determine if this would occlude the effects of SCP released from B38 during a tetanus. We found that exogenous SCP dramatically reduced PTP for B38 but had little effect on PTP for B3. Thus our results support the hypothesis that physiological stimulation of B38 elicits PTP that is predominantly dependent on the release of SCP from its own terminals. They also demonstrate that the mechanisms underlying PTP can be very different for two motor neurons innervating the same target muscle.

scholarly journals ZBP1 induces inflammatory signaling via RIPK3 and promotes SARS-CoV-2-induced cytokine expression

2021 ◽  
Author(s):  
Ruoshi Peng ◽  
Xuan Wang-Kan ◽  
Manja Idorn ◽  
Felix Y Zhou ◽  
Susana L Orozco ◽  
...  
Keyword(s):  
Cell Death ◽  
Signaling Pathway ◽  
Kinase Activity ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Innate Immune Responses ◽  
Inflammatory Signaling ◽  
Antiviral Responses ◽  
Nucleic Acid Sensor ◽  
Activity Dependent

AbstractCOVID-19 caused by the SARS-CoV-2 virus remains a threat to global health. The disease severity is mediated by cell death and inflammation, which regulate both the antiviral and the pathological innate immune responses. ZBP1, an interferon-induced cytosolic nucleic acid sensor, facilitates antiviral responses via RIPK3. Although ZBP1-mediated cell death is widely described, whether and how it promotes inflammatory signaling is unclear. Here, we report a ZBP1-induced inflammatory signaling pathway that depends on ubiquitination and RIPK3’s scaffolding ability independently of cell death. In human cells, ZBP1 associates with RIPK1 and RIPK3 as well as ubiquitin ligases cIAP1 and LUBAC. RIPK1 and ZBP1 are ubiquitinated to promote TAK1- and IKK-mediated inflammatory signaling. Additionally, RIPK1 recruits the p43/41-caspase-8-p43-FLIP heterodimer to suppress RIPK3 kinase activity, which otherwise promotes inflammatory signaling in a kinase activity-dependent manner. Lastly, we show that ZBP1 contributes to SARS-CoV-2-induced cytokine production. Taken together, we describe a ZBP1-RIPK1-RIPK3-mediated inflammatory signaling pathway relayed by the scaffolding role of RIPKs and regulated by caspase-8. Our results suggest the ZBP1 pathway contributes to inflammation in response to SARS-CoV-2 infection.

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