scholarly journals Neuronal autophagy regulates presynaptic neurotransmission by controlling the axonal endoplasmic reticulum

2020 ◽  
Author(s):  
Marijn Kuijpers ◽  
Gaga Kochlamazashvili ◽  
Alexander Stumpf ◽  
Dmytro Puchkov ◽  
Max Thomas Lucht ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Calcium Stores ◽  
Synaptic Neurotransmission ◽  
Excitatory Neurotransmission ◽  
Electrical Impulses ◽  
The Brain ◽  
Neuronal Autophagy

SUMMARYInformation processing in the brain is encoded as electrical impulses in neurons that are relayed from the presynaptic compartment to postsynaptic neurons by regulated neurotransmitter release. Neurons are known to rely on autophagy for the removal of defective proteins or organelles to maintain synaptic neurotransmission and to counteract neurodegeneration. In spite of its importance for neuronal health, the physiological substrates of neuronal autophagy in the absence of proteotoxic challenge have remained largely elusive. We use knockout mice conditionally lacking the essential autophagy protein ATG5 and quantitative proteomics to demonstrate that loss of neuronal autophagy causes the selective accumulation of tubular endoplasmic reticulum (ER) in axons, resulting in increased excitatory neurotransmission and compromised postnatal viability in vivo. The gain in excitatory neurotransmission is shown to be a consequence of elevated calcium release from ER stores via ryanodine receptors accumulated in axons and at presynaptic sites. We propose a model in which neuronal autophagy controls axonal ER calcium stores to regulate neurotransmission in healthy neurons and in the brain.

scholarly journals Drug library screen identifies inhibitors of toxic astrogliosis

2020 ◽  
Author(s):  
Ruturaj R Masvekar ◽  
Peter R Kosa ◽  
Christopher Barbour ◽  
Joshua L Milstein ◽  
Bibiana Bielekova
Keyword(s):  
Multiple Sclerosis ◽  
Endoplasmic Reticulum ◽  
Cerebrospinal Fluid ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Multiple Sclerosis Patients

Objective: Multiple sclerosis is a chronic neuroinflammatory disorder, in which activated immune cells directly or indirectly induce demyelination and axonal degradation. Inflammatory stimuli also change the phenotype of astrocytes, making them neurotoxic. The resulting toxic astrocyte phenotype has been observed in animal models of neuroinflammation and in multiple sclerosis lesions. Proteins secreted by toxic astrocytes are elevated in the cerebrospinal fluid of multiple sclerosis patients and reproducibly correlate with the rates of accumulation of neurological disability and brain atrophy. This suggests a pathogenic role for neurotoxic astrocytes in multiple sclerosis. Methods: Here, we applied a commercially available library of small molecules that are either Food and Drug Administration-approved or in clinical development to an in vitro model of toxic astrogliosis to identify drugs and signaling pathways that inhibit inflammatory transformation of astrocytes to a neurotoxic phenotype. Results: Inhibitors of three pathways related to the endoplasmic reticulum stress: 1) proteasome, 2) heat shock protein 90 and 3) mammalian target of rapamycin reproducibly decreased inflammation-induced conversion of astrocytes to toxic phenotype. Dantrolene, an anti-spasticity drug that inhibits calcium release through ryanodine receptors expressed in the endoplasmic reticulum of central nervous system cells, also exerted inhibitory effect at in vivo achievable concentrations. Finally, we established cerebrospinal fluid SERPINA3 as a relevant pharmacodynamic marker for inhibiting toxic astrocytes in clinical trials. Interpretation: Drug library screening provides mechanistic insight into the generation of toxic astrocytes and identifies candidates for immediate proof-of-principle clinical trial(s).

Heterologous expression of polycystin-1 inhibits endoplasmic reticulum calcium leak in stably transfected MDCK cells

2008 ◽  
Vol 294 (6) ◽  
pp. F1279-F1286 ◽  
Author(s):  
Kimberly H. Weber ◽  
Eun Kyung Lee ◽  
Uma Basavanna ◽  
Sabina Lindley ◽  
Roy C. Ziegelstein ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Calcium Release ◽  
Mdck Cells ◽  
Calcium Ionophore ◽  
Calcium Flux ◽  
Calcium Stores ◽  
Endoplasmic Reticulum Calcium ◽  
Calcium Indicator ◽  
Luminal Calcium ◽  
Er Membrane

We previously found that polycystin-1 accelerated the decay of ligand-activated cytoplasmic calcium transients through enhanced reuptake of calcium into the endoplasmic reticulum (ER; Hooper KM, Boletta A, Germino GG, Hu Q, Ziegelstein RC, Sutters M. Am J Physiol Renal Physiol 289: F521–F530, 2005). Calcium flux across the ER membrane is determined by the balance of active uptake and passive leak. In the present study, we show that polycystin-1 inhibited calcium leak across the ER membrane, an effect that would explain the capacity of this protein to accelerate clearance of calcium from the cytoplasm following a calcium release response. Calcium leak was detected by measurement of the accumulation of calcium in the cytoplasm following treatment with thapsigargin. Heterologous polycystin-1, stably expressed in Madin-Darby canine kidney cells, attenuated the thapsigargin-induced calcium peak with no effect on basal calcium stores, mitochondrial calcium uptake, or extrusion of calcium across the plasma membrane. The capacity of polycystin-1 to limit the rate of decay of ER luminal calcium following inhibition of the pump was shown indirectly using the calcium ionophore ionomycin, and directly by loading the ER with a low-affinity calcium indicator. We conclude that disruption of ER luminal calcium homeostasis may contribute to the cyst phenotype in autosomal dominant polycystic kidney disease.

scholarly journals The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity

2021 ◽  
Author(s):  
Dinh Thi Nguyen ◽  
Thuong Manh Le ◽  
Tsuyoshi Hattori ◽  
Mika Takarada-Iemata ◽  
Hiroshi Ishii ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Hippocampal Neurons ◽  
Neuronal Survival ◽  
Binding Capacity ◽  
Critical Role ◽  
Er Stress Response ◽  
The Central Nervous System ◽  
The Brain

AbstractWhile ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of ATF6β is largely unknown. Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin, a molecular chaperone in the ER with a high Ca2+-binding capacity. Calreticulin expression was reduced to ~50% in the central nervous system of Atf6b−/− mice, and restored by ATF6β. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death, which was rescued by ATF6β, calreticulin, Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in hippocampi of Atf6b−/− and Calr+/− mice, and restored by 2-APB and salubrinal. These results suggest that the ATF6β-calreticulin axis plays a critical role in the neuronal survival by improving Ca2+ homeostasis under ER stress.

scholarly journals Bring it back, bring it back, don't take it away from me – the sorting receptor RER1

2020 ◽  
Vol 133 (17) ◽  
pp. jcs231423
Author(s):  
Wim Annaert ◽  
Christoph Kaether
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Biology ◽  
Mammalian Cells ◽  
Future Directions ◽  
Binding Motifs ◽  
Sorting Receptor ◽  
Intermediate Compartment ◽  
The Brain

ABSTRACTThe quote “bring it back, bring it back, don't take it away from me” from Queen's Love of my life describes the function of the sorting receptor RER1, a 23 kDa protein with four transmembrane domains (TMDs) that localizes to the intermediate compartment and the cis-Golgi. From there it returns escaped proteins that are not supposed to leave the endoplasmic reticulum (ER) back to it. Unique about RER1 is its ability to recognize its ligands through binding motifs in TMDs. Among its substrates are ER-resident proteins, as well as unassembled subunits of multimeric complexes that are retrieved back into the ER, this way guarding the full assembly of their respective complexes. The basic mechanisms for RER1-dependent retrieval have been already elucidated some years ago in yeast. More recently, several important cargoes of RER1 have been described in mammalian cells, and the in vivo role of RER1 is being unveiled by using mouse models. In this Review, we give an overview of the cell biology of RER1 in different models, discuss its controversial role in the brain and provide an outlook on future directions for RER1 research.

Metabotropic glutamate receptor-mediated cyclic ADP ribose signalling

2015 ◽  
Vol 43 (3) ◽  
pp. 405-409 ◽  
Author(s):  
Aidan Kaar ◽  
Mark G. Rae
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Calcium Release ◽  
Metabotropic Glutamate Receptor ◽  
Ryanodine Receptors ◽  
Calcium Stores ◽  
Ip3 Receptors ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Cyclic Adp Ribose ◽  
Key Aspects

Group I metabotropic glutamate receptors (I-mGluRs) modulate numerous cellular functions such as specific membrane currents and neurotransmitter release linked to their ability to mobilize calcium from intracellular calcium stores. As such, most I-mGluR research to date has focused on the coupling of these receptors to phospholipase C (PLC)-dependent and inositol (1,4,5) trisphosphate (IP3)-mediated calcium release via activation of IP3 receptors located upon the sarco/endoplasmic reticulum. However, there are now numerous examples of PLC- and IP3-independent I-mGluR-evoked signals, which may instead be mediated by activation of ryanodine receptors (RyRs). A prime candidate for mediating this coupling between I-mGluR activation and RyR opening is cyclic ADP ribose (cADPR) and, indeed, several of these PLC-/IP3-independent I-mGluR-evoked calcium signals have now been shown to be mediated wholly or partly by cADPR-evoked activation of RyRs. The contribution of cADPR signalling to I-mGluR-mediated responses is relatively complex, dependent as it is on factors such as cell type, excitation state of the cell and location of I-mGluRs on the cell. However, these factors notwithstanding, I-mGluR-mediated cADPR signalling remains poorly characterized, with several key aspects yet to be fully elucidated such as (1) the range of stimuli which evoke cADPR production, (2) the specific molecular mechanism(s) coupling cADPR to RyR activation and (3) the contribution of cADPR-mediated responses to downstream outputs such as synaptic plasticity. Furthermore, it is possible that the cADPR pathway may play a role in diseases underpinned by dysregulated calcium homoeostasis such as Alzheimer's disease (AD).

scholarly journals Calcium signaling via two-pore channels: local or global, that is the question

2010 ◽  
Vol 298 (3) ◽  
pp. C430-C441 ◽  
Author(s):  
Michael X. Zhu ◽  
Jianjie Ma ◽  
John Parrington ◽  
Peter J. Calcraft ◽  
Antony Galione ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Calcium Stores ◽  
Calcium Signals ◽  
Calcium Release Channels ◽  
Intracellular Calcium Signaling ◽  
Global Signal ◽  
Rna Knockdown ◽  
Calcium Induced Calcium Release

Recently, we identified, for the first time, two-pore channels (TPCs, TPCN for gene name) as a novel family of nicotinic acid adenine dinucleotide phosphate (NAADP)-gated, endolysosome-targeted calcium release channels. Significantly, three subtypes of TPCs have been characterized, TPC1-3, with each being targeted to discrete acidic calcium stores, namely lysosomes (TPC2) and endosomes (TPC1 and TPC3). That TPCs act as NAADP-gated calcium release channels is clear, given that NAADP binds to high- and low-affinity sites associated with TPC2 and thereby induces calcium release and homologous desensitization, as observed in the case of endogenous NAADP receptors. Moreover, NAADP-evoked calcium signals via TPC2 are ablated by short hairpin RNA knockdown of TPC2 and by depletion of acidic calcium stores with bafilomycin. Importantly, however, NAADP-evoked calcium signals were biphasic in nature, with an initial phase of calcium release from lysosomes via TPC2, being subsequently amplified by calcium-induced calcium release (CICR) from the endoplasmic reticulum (ER). In marked contrast, calcium release via endosome-targeted TPC1 induced only spatially restricted calcium signals that were not amplified by CICR from the ER. These findings provide new insights into the mechanisms that cells may utilize to “filter” calcium signals via junctional complexes to determine whether a given signal remains local or is converted into a propagating global signal. Essentially, endosomes and lysosomes represent vesicular calcium stores, quite unlike the ER network, and TPCs do not themselves support CICR or, therefore, propagating regenerative calcium waves. Thus “quantal” vesicular calcium release via TPCs must subsequently recruit inositol 1,4,5-trisphoshpate receptors and/or ryanodine receptors on the ER by CICR to evoke a propagating calcium wave. This may call for a revision of current views on the mechanisms of intracellular calcium signaling. The purpose of this review is, therefore, to provide an appropriate framework for future studies in this area.

scholarly journals Role of ERO1-α–mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress–induced apoptosis

2009 ◽  
Vol 186 (6) ◽  
pp. 783-792 ◽  
Author(s):  
Gang Li ◽  
Marco Mongillo ◽  
King-Tung Chin ◽  
Heather Harding ◽  
David Ron ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Calcium Release ◽  
Loss Of Function ◽  
Ip3 Receptor ◽  
Calcium Dependent ◽  
Insulin Resistant ◽  
Stressed Cells ◽  
Induced Apoptosis

Endoplasmic reticulum (ER) stress–induced apoptosis is involved in many diseases, but the mechanisms linking ER stress to apoptosis are incompletely understood. Based on roles for C/EPB homologous protein (CHOP) and ER calcium release in apoptosis, we hypothesized that apoptosis involves the activation of inositol 1,4,5-triphosphate (IP3) receptor (IP3R) via CHOP-induced ERO1-α (ER oxidase 1 α). In ER-stressed cells, ERO1-α is induced by CHOP, and small interfering RNA (siRNA) knockdown of ERO1-α suppresses apoptosis. IP3-induced calcium release (IICR) is increased during ER stress, and this response is blocked by siRNA-mediated silencing of ERO1-α or IP3R1 and by loss-of-function mutations in Ero1a or Chop. Reconstitution of ERO1-α in Chop−/− macrophages restores ER stress–induced IICR and apoptosis. In vivo, macrophages from wild-type mice but not Chop−/− mice have elevated IICR when the animals are challenged with the ER stressor tunicamycin. Macrophages from insulin-resistant ob/ob mice, another model of ER stress, also have elevated IICR. These data shed new light on how the CHOP pathway of apoptosis triggers calcium-dependent apoptosis through an ERO1-α–IP3R pathway.

scholarly journals Intracellular Ca2+ stores can account for the time course of LTP induction: a model of Ca2+ dynamics in dendritic spines

1995 ◽  
Vol 74 (3) ◽  
pp. 1046-1055 ◽  
Author(s):  
A. Schiegg ◽  
W. Gerstner ◽  
R. Ritz ◽  
J. L. van Hemmen
Keyword(s):  
Hippocampal Neurons ◽  
Time Course ◽  
Calcium Release ◽  
Model Simulation ◽  
Ryanodine Receptors ◽  
Long Term Potentiation ◽  
Calcium Stores ◽  
Calcium Source ◽  
The One

1. A model of Ca2+ dynamics in spines of CA1 hippocampal neurons is presented. In contrast to traditional models, which concentrate on the effects of Ca2+ influx, diffusion, buffering, and extrusion, we also consider the additional effect of intracellular Ca2+ stores. 2. It is shown that traditional models without Ca2+ stores cannot account for the time course of long-term potentiation (LTP) induction as found in recent experiments. Experimental data suggest that the intracellular Ca2+ concentration should be elevated for up to 2 s, whereas the Ca2+ concentration in standard models of Ca2+ dynamics decays much faster. 3. When intracellular Ca2+ stores are taken into account, a much slower decay is found. In particular, a model simulation with a stimulation paradigm consisting of two bursts of four impulses at 100 Hz each and variable interburst intervals can reproduce experimental results found for primed or theta-burst stimulation. 4. In our model, Ca2+ release from the store has a nonlinear, bell-shaped dependence on the intracellular Ca2+ concentration, similar to the one found for inositoltrisphosphate and ryanodine receptors. These receptors are known to control calcium release from intracellular stores. 5. Our model suggests an important role of intracellular calcium stores in the induction of LTP. The stores serve as a long-term calcium source that can sustain an intracellular Ca2+ concentration above the resting level for 1-2 s.

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