scholarly journals Neurexins regulate presynaptic GABAB-receptors at central synapses

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Fujun Luo ◽  
Alessandra Sclip ◽  
Sean Merrill ◽  
Thomas C. Südhof
Keyword(s):  
Active Zone ◽  
Neurotransmitter Release ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Receptor Activation ◽  
Gabab Receptors ◽  
Inhibitory Synapses ◽  
Receptor Signaling ◽  
Ca1 Region ◽  
Presynaptic Active Zone

AbstractDiverse signaling complexes are precisely assembled at the presynaptic active zone for dynamic modulation of synaptic transmission and synaptic plasticity. Presynaptic GABAB-receptors nucleate critical signaling complexes regulating neurotransmitter release at most synapses. However, the molecular mechanisms underlying assembly of GABAB-receptor signaling complexes remain unclear. Here we show that neurexins are required for the localization and function of presynaptic GABAB-receptor signaling complexes. At four model synapses, excitatory calyx of Held synapses in the brainstem, excitatory and inhibitory synapses on hippocampal CA1-region pyramidal neurons, and inhibitory basket cell synapses in the cerebellum, deletion of neurexins rendered neurotransmitter release significantly less sensitive to GABAB-receptor activation. Moreover, deletion of neurexins caused a loss of GABAB-receptors from the presynaptic active zone of the calyx synapse. These findings extend the role of neurexins at the presynaptic active zone to enabling GABAB-receptor signaling, supporting the notion that neurexins function as central organizers of active zone signaling complexes.

scholarly journals Jacob, a Synapto-Nuclear Protein Messenger Linking N-methyl-D-aspartate Receptor Activation to Nuclear Gene Expression

2021 ◽  
Vol 13 ◽  
Author(s):  
Katarzyna M. Grochowska ◽  
Julia Bär ◽  
Guilherme M. Gomes ◽  
Michael R. Kreutz ◽  
Anna Karpova
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Protein Transport ◽  
Pyramidal Neurons ◽  
Temporal Integration ◽  
Dendritic Tree ◽  
Nuclear Gene ◽  
Receptor Activation ◽  
Excitatory Input ◽  
Splice Isoforms

Pyramidal neurons exhibit a complex dendritic tree that is decorated by a huge number of spine synapses receiving excitatory input. Synaptic signals not only act locally but are also conveyed to the nucleus of the postsynaptic neuron to regulate gene expression. This raises the question of how the spatio-temporal integration of synaptic inputs is accomplished at the genomic level and which molecular mechanisms are involved. Protein transport from synapse to nucleus has been shown in several studies and has the potential to encode synaptic signals at the site of origin and decode them in the nucleus. In this review, we summarize the knowledge about the properties of the synapto-nuclear messenger protein Jacob with special emphasis on a putative role in hippocampal neuronal plasticity. We will elaborate on the interactome of Jacob, the signals that control synapto-nuclear trafficking, the mechanisms of transport, and the potential nuclear function. In addition, we will address the organization of the Jacob/NSMF gene, its origin and we will summarize the evidence for the existence of splice isoforms and their expression pattern.

scholarly journals S6 kinase localizes to the presynaptic active zone and functions with PDK1 to control synapse development

2011 ◽  
Vol 194 (6) ◽  
pp. 921-935 ◽  
Author(s):  
Ling Cheng ◽  
Cody Locke ◽  
Graeme W. Davis
Keyword(s):  
Active Zone ◽  
Neurotransmitter Release ◽  
Synaptic Function ◽  
Growth Factor Signaling ◽  
Neuron Type ◽  
S6 Kinase ◽  
Neuronal Dendrites ◽  
Presynaptic Boutons ◽  
Presynaptic Active Zone ◽  
Presynaptic Protein

The dimensions of neuronal dendrites, axons, and synaptic terminals are reproducibly specified for each neuron type, yet it remains unknown how these structures acquire their precise dimensions of length and diameter. Similarly, it remains unknown how active zone number and synaptic strength are specified relative the precise dimensions of presynaptic boutons. In this paper, we demonstrate that S6 kinase (S6K) localizes to the presynaptic active zone. Specifically, S6K colocalizes with the presynaptic protein Bruchpilot (Brp) and requires Brp for active zone localization. We then provide evidence that S6K functions downstream of presynaptic PDK1 to control synaptic bouton size, active zone number, and synaptic function without influencing presynaptic bouton number. We further demonstrate that PDK1 is also a presynaptic protein, though it is distributed more broadly. We present a model in which synaptic S6K responds to local extracellular nutrient and growth factor signaling at the synapse to modulate developmental size specification, including cell size, bouton size, active zone number, and neurotransmitter release.

scholarly journals Somatic and dendritic GABAB receptors regulate neuronal excitability via different mechanisms

2012 ◽  
Vol 108 (10) ◽  
pp. 2810-2818 ◽  
Author(s):  
Jean-Didier Breton ◽  
Greg J. Stuart
Keyword(s):  
Potassium Channels ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Barrel Cortex ◽  
Receptor Activation ◽  
Gabab Receptors ◽  
Membrane Properties ◽  
Dendritic Excitability ◽  
The Impact ◽  
Neuronal Output

GABAB receptors play a key role in regulating neuronal excitability in the brain. Whereas the impact of somatic GABAB receptors on neuronal excitability has been studied in some detail, much less is known about the role of dendritic GABAB receptors. Here, we investigate the impact of GABAB receptor activation on the somato-dendritic excitability of layer 5 pyramidal neurons in the rat barrel cortex. Activation of GABAB receptors led to hyperpolarization and a decrease in membrane resistance that was greatest at somatic and proximal dendritic locations. These effects were occluded by low concentrations of barium (100 μM), suggesting that they are mediated by potassium channels. In contrast, activation of dendritic GABAB receptors decreased the width of backpropagating action potential (APs) and abolished dendritic calcium electrogenesis, indicating that dendritic GABAB receptors regulate excitability, primarily via inhibition of voltage-dependent calcium channels. These distinct actions of somatic and dendritic GABAB receptors regulated neuronal output in different ways. Activation of somatic GABAB receptors led to a reduction in neuronal output, primarily by increasing the AP rheobase, whereas activation of dendritic GABAB receptors blocked burst firing, decreasing AP output in the absence of a significant change in somatic membrane properties. Taken together, our results show that GABAB receptors regulate somatic and dendritic excitability of cortical pyramidal neurons via different cellular mechanisms. Somatic GABAB receptors activate potassium channels, leading primarily to a subtractive or shunting form of inhibition, whereas dendritic GABAB receptors inhibit dendritic calcium electrogenesis, leading to a reduction in bursting firing.

scholarly journals Estrogen receptors promote NSCLC progression by modulating the membrane receptor signaling network: a systems biology perspective

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Xiujuan Gao ◽  
Yue Cai ◽  
Zhuo Wang ◽  
Wenjuan He ◽  
Sisi Cao ◽  
...  
Keyword(s):  
Systems Biology ◽  
Estrogen Receptors ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
Signaling Network ◽  
Membrane Receptor ◽  
Receptor Signaling ◽  
Molecular Signaling ◽  
Cell Behaviors ◽  
Cancer Systems Biology

Abstract Background Estrogen receptors (ERs) are thought to play an important role in non-small cell lung cancer (NSCLC). However, the effect of ERs in NSCLC is still controversial and needs further investigation. A new consideration is that ERs may affect NSCLC progression through complicated molecular signaling networks rather than individual targets. Therefore, this study aims to explore the effect of ERs in NSCLC from the perspective of cancer systems biology. Methods The gene expression profile of NSCLC samples in TCGA dataset was analyzed by bioinformatics method. Variations of cell behaviors and protein expression were detected in vitro. The kinetic process of molecular signaling network was illustrated by a systemic computational model. At last, immunohistochemical (IHC) and survival analysis was applied to evaluate the clinical relevance and prognostic effect of key receptors in NSCLC. Results Bioinformatics analysis revealed that ERs might affect many cancer-related molecular events and pathways in NSCLC, particularly membrane receptor activation and signal transduction, which might ultimately lead to changes in cell behaviors. Experimental results confirmed that ERs could regulate cell behaviors including cell proliferation, apoptosis, invasion and migration; ERs also regulated the expression or activation of key members in membrane receptor signaling pathways such as epidermal growth factor receptor (EGFR), Notch1 and Glycogen synthase kinase-3β/β-Catenin (GSK3β/β-Catenin) pathways. Modeling results illustrated that the promotive effect of ERs in NSCLC was implemented by modulating the signaling network composed of EGFR, Notch1 and GSK3β/β-Catenin pathways; ERs maintained and enhanced the output of oncogenic signals by adding redundant and positive-feedback paths into the network. IHC results echoed that high expression of ERs, EGFR and Notch1 had a synergistic effect on poor prognosis of advanced NSCLC. Conclusions This study indicated that ERs were likely to promote NSCLC progression by modulating the integrated membrane receptor signaling network composed of EGFR, Notch1 and GSK3β/β-Catenin pathways and then affecting tumor cell behaviors. It also complemented the molecular mechanisms underlying the progression of NSCLC and provided new opportunities for optimizing therapeutic scheme of NSCLC.

scholarly journals The Role of Androgen Receptor Signaling in Ovarian Cancer

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 176 ◽  
Author(s):  
Taichi Mizushima ◽  
Hiroshi Miyamoto
Keyword(s):  
Ovarian Cancer ◽  
Androgen Receptor ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
Receptor Signaling ◽  
Therapeutic Approaches ◽  
Androgen Receptor Signaling ◽  
Ovarian Carcinogenesis ◽  
Androgen Receptor Activity

Emerging evidence has suggested that androgen receptor signaling plays an important role in ovarian cancer outgrowth. Specifically, androgen receptor activation appears to be associated with increased risks of developing ovarian cancer and inducing tumor progression. However, conflicting findings have also been reported. This review summarizes and discusses the available data indicating the involvement of androgens as well as androgen receptor and related signals in ovarian carcinogenesis and cancer growth. Although the underlying molecular mechanisms for androgen receptor functions in ovarian cancer remain far from being fully understood, current observations may offer effective chemopreventive and therapeutic approaches, via modulation of androgen receptor activity, against ovarian cancer. Indeed, several clinical trials have been conducted to determine the efficacy of androgen deprivation therapy in patients with ovarian cancer.

scholarly journals Tonic Activation of GABAB Receptors Reduces Release Probability at Inhibitory Connections in the Cerebellar Glomerulus

2009 ◽  
Vol 101 (6) ◽  
pp. 3089-3099 ◽  
Author(s):  
Lisa Mapelli ◽  
Paola Rossi ◽  
Thierry Nieus ◽  
Egidio D'Angelo
Keyword(s):  
Neurotransmitter Release ◽  
Mossy Fiber ◽  
Signal Transmission ◽  
Receptor Activation ◽  
Gabab Receptors ◽  
Dynamic Regulation ◽  
Release Probability ◽  
Receptor Modulation ◽  
Tonic Activation ◽  
Ambient Gaba

In the cerebellum, granule cells are inhibited by Golgi cells through GABAergic synapses generating complex responses involving both phasic neurotransmitter release and the establishment of ambient γ-aminobutyric acid (GABA) levels. Although at this synapse the mechanisms of postsynaptic integration have been clarified to a considerable extent, the mechanisms of neurotransmitter release remained largely unknown. Here we have investigated the quantal properties of release during repetitive neurotransmission, revealing that tonic GABAB receptor activation by ambient GABA regulates release probability. Blocking GABAB receptors with CGP55845 enhanced the first inhibitory postsynaptic current (IPSC) and short-term depression in a train while reducing trial-to-trial variability and failures. The changes caused by CGP55845 were similar to those caused by increasing extracellular Ca2+ concentration, in agreement with a presynaptic GABAB receptor modulation of release probability. However, the slow tail following IPSC peak demonstrated a remarkable temporal summation and was not modified by CGP55845 or extracellular Ca2+ increase. This result shows that tonic activation of presynaptic GABAB receptors by ambient GABA selectively regulates the onset of inhibition bearing potential consequences for the dynamic regulation of signal transmission through the mossy fiber–granule cell pathway of the cerebellum.

RIM function in short- and long-term synaptic plasticity

2005 ◽  
Vol 33 (6) ◽  
pp. 1345-1349 ◽  
Author(s):  
P.S. Kaeser ◽  
T.C. Südhof
Keyword(s):  
Synaptic Plasticity ◽  
Active Zone ◽  
Neurotransmitter Release ◽  
Mossy Fibre ◽  
Short Term ◽  
Parallel Fibre ◽  
Ca1 Region ◽  
Gabaergic Synapses ◽  
Protein Rich

RIM1α (Rab3-interacting molecule 1α) is a large multidomain protein that is localized to presynaptic active zones [Wang, Okamoto, Schmitz, Hofmann and Südhof (1997) Nature (London) 388, 593–598] and is the founding member of the RIM protein family that also includes RIM2α, 2β, 2γ, 3γ and 4γ [Wang and Südhof (2003) Genomics 81, 126–137]. In presynaptic nerve termini, RIM1α interacts with a series of presynaptic proteins, including the synaptic vesicle GTPase Rab3 and the active zone proteins Munc13, liprins and ELKS (a protein rich in glutamate, leucine, lysine and serine). Mouse KOs (knockouts) revealed that, in different types of synapses, RIM1α is essential for different forms of synaptic plasticity. In CA1-region Schaffer-collateral excitatory synapses and in GABAergic synapses (where GABA is γ-aminobutyric acid), RIM1α is required for maintaining normal neurotransmitter release and short-term synaptic plasticity. In contrast, in excitatory CA3-region mossy fibre synapses and cerebellar parallel fibre synapses, RIM1α is necessary for presynaptic long-term, but not short-term, synaptic plasticity. In these synapses, the function of RIM1α in presynaptic long-term plasticity depends, at least in part, on phosphorylation of RIM1α at a single site, suggesting that RIM1α constitutes a ‘phosphoswitch’ that determines synaptic strength. However, in spite of the progress in understanding RIM1α function, the mechanisms by which RIM1α acts remain unknown. For example, how does phosphorylation regulate RIM1α, what is the relationship of the function of RIM1α in basic release to synaptic plasticity and what is the physiological significance of different forms of RIM-dependent plasticity? Moreover, the roles of other RIM isoforms are unclear. Addressing these important questions will contribute to our view of how neurotransmitter release is regulated at the presynaptic active zone.

scholarly journals Distinct mechanisms underlie the subsynaptic mobility of presynaptic metabotropic glutamate receptor types to tune receptor activation

2020 ◽  
Author(s):  
Anna Bodzęta ◽  
Florian Berger ◽  
Harold D. MacGillavry
Keyword(s):  
Synaptic Transmission ◽  
Active Zone ◽  
Metabotropic Glutamate Receptors ◽  
Molecular Mechanisms ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Activation ◽  
Synaptic Activity ◽  
Control Surface ◽  
Metabotropic Glutamate ◽  
Surface Mobility

ABSTRACTPresynaptic metabotropic glutamate receptors (mGluRs) are essential for activity-dependent modulation of synaptic transmission in the brain. However, the mechanisms that control the subsynaptic distribution and mobility of these receptors to contribute to their function are poorly understood. Here, using super-resolution microscopy and single-molecule tracking, we provide novel insights in the molecular mechanisms that control the spatial distribution and mobility of presynaptic mGluRs. We demonstrate that mGluR2 localizes diffusely along the axon and boutons and is highly mobile, while mGluR7 is immobilized specifically at the active zone, indicating that distinct mechanisms underlie the dynamic distribution of these receptor types. Indeed, we found that the positioning of mGluR2 is modulated by intracellular interactions. In contrast, immobilization of mGluR7 at the active zone is mediated by its extracellular domain that interacts in trans with the postsynaptic adhesion molecule ELFN2. Moreover, we found that receptor activation or changing synaptic activity does not alter the surface mobility of presynaptic mGluRs. Additionally, computational modeling of presynaptic mGluRs activity revealed that the precise subsynaptic localization of mGluRs determines their activation probability and thus directly impacts their ability to modulate neurotransmitter release. Altogether, this study demonstrates that distinct mechanisms control surface mobility of presynaptic mGluRs to differentially contribute to the regulation of glutamatergic synaptic transmission.

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