Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Fast endocytosis is inhibited by GABA-mediated chloride influx at a presynaptic terminal.

ABSTRACT: Although multiple kinetic components of synaptic vesicle endocytosis have been identified, it has remained unclear whether neurons can differentially modulate these components. Using membrane capacitance measurements from isolated goldfish bipolar cell terminals, we found that the kinetics of endocytosis in retinal slices (single exponential decay; tau > 10 s) were significantly slower than those in acutely dissociated terminals (double exponential decay; tau(fast) approximately 1-2 s; tau(slow) > 10 s). Surprisingly, GABA(A) and/or GABA(C) receptor antagonists restored the fast component of endocytosis to terminals in retinal slices. Blocking GABAergic feedback from reciprocal synapses or removing external Cl(-) ions also allowed for fast endocytosis. Elevating internal Cl(-) via the patch pipette invariably slowed endocytosis, even in terminals dialyzed with increased Ca(2+) buffer. These results suggest a new role for GABA and Cl(-) ions in blocking the trigger for fast endocytosis at this ribbon-type synapse.

SUBMITTER: Hull C

PROVIDER: S-EPMC3572843 | biostudies-literature | 2004 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Fast endocytosis is inhibited by GABA-mediated chloride influx at a presynaptic terminal.

Hull Court C von Gersdorff Henrique H

Neuron 20041001 3

Although multiple kinetic components of synaptic vesicle endocytosis have been identified, it has remained unclear whether neurons can differentially modulate these components. Using membrane capacitance measurements from isolated goldfish bipolar cell terminals, we found that the kinetics of endocytosis in retinal slices (single exponential decay; tau > 10 s) were significantly slower than those in acutely dissociated terminals (double exponential decay; tau(fast) approximately 1-2 s; tau(slow) ...[more]

PMID: 15504327

Similar Datasets

Clathrin-mediated endocytosis is inhibited during mitosis.

Project description:A long-standing paradigm in cell biology is the shutdown of endocytosis during mitosis. There is consensus that transferrin uptake is inhibited after entry into prophase and that it resumes in telophase. A recent study proposed that endocytosis is continuous throughout the cell cycle and that the observed inhibition of transferrin uptake is due to a decrease in available transferrin receptor at the cell surface, and not to a shutdown of endocytosis. This challenge to the established view is gradually becoming accepted. Because of this controversy, we revisited the question of endocytic activity during mitosis. Using an antibody uptake assay and controlling for potential changes in surface receptor density, we demonstrate the strong inhibition of endocytosis in mitosis of CD8 chimeras containing any of the three major internalization motifs for clathrin-mediated endocytosis (YXX?, [DE]XXXL[LI], or FXNPXY) or a CD8 protein with the cytoplasmic tail of the cation-independent mannose 6-phosphate receptor. The shutdown is not gradual: We describe a binary switch from endocytosis being "on" in interphase to "off" in mitosis as cells traverse the G(2)/M checkpoint. In addition, we show that the inhibition of transferrin uptake in mitosis occurs despite abundant transferrin receptor at the surface of HeLa cells. Our study finds no support for the recent idea that endocytosis continues during mitosis, and we conclude that endocytosis is temporarily shutdown during early mitosis.

| S-EPMC3340072 | biostudies-literature

Chloride influx aggravates Ca2+-dependent AMPA receptor-mediated motoneuron death.

Project description:AMPA receptor-mediated excitotoxicity has been implicated in the pathogenesis of stroke, neurotrauma, epilepsy, and many neurodegenerative diseases such as motoneuron disease. We studied the role of Cl- in AMPA receptor-mediated Ca2+-dependent excitotoxicity in cultured rat spinal motoneurons. Using the gramicidin perforated patch-clamp technique, the intracellular Cl- concentration could be calculated from the reversal potential of the GABA-induced current. The membrane depolarization caused by AMPA receptor stimulation resulted in Cl- influx through 5-nitro-2(3-phenylpropyl-amino) benzoic acid- and niflumic acid-sensitive Cl- channels. Cl- influx during AMPA receptor stimulation aggravated excitotoxic motoneuron death by two mechanisms: an increase of AMPA receptor conductance and an elevation of the Ca2+ driving force through a partial repolarization. The Cl- influx during AMPA receptor stimulation was enhanced by coadministration of GABA. This resulted in an increased Ca2+ influx and an enhanced cell death, suggesting that concomitant GABAergic stimulation may aggravate excitotoxic motoneuron death.

| S-EPMC6741175 | biostudies-literature

Molecular mechanism of Fast Endophilin-Mediated Endocytosis.

Project description:Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Clathrin-mediated endocytosis (CME) is the housekeeping pathway in resting cells but additional Clathrin-independent endocytic (CIE) routes, including Fast Endophilin-Mediated Endocytosis (FEME), internalize specific cargoes and support diverse cellular functions. FEME is part of the Dynamin-dependent subgroup of CIE pathways. Here, we review our current understanding of the molecular mechanism of FEME. Key steps are: (i) priming, (ii) cargo selection, (iii) membrane curvature and carrier formation, (iv) membrane scission and (v) cytosolic transport. All steps are controlled by regulatory mechanisms mediated by phosphoinositides and by kinases such as Src, LRRK2, Cdk5 and GSK3?. A key feature of FEME is that it is not constitutively active but triggered upon the stimulation of selected cell surface receptors by their ligands. In resting cells, there is a priming cycle that concentrates Endophilin into clusters on discrete locations of the plasma membrane. In the absence of receptor activation, the patches quickly abort and new cycles are initiated nearby, constantly priming the plasma membrane for FEME. Upon activation, receptors are swiftly sorted into pre-existing Endophilin clusters, which then bud to form FEME carriers within 10?s. We summarize the hallmarks of FEME and the techniques and assays required to identify it. Next, we review similarities and differences with other CIE pathways and proposed cargoes that may use FEME to enter cells. Finally, we submit pending questions and future milestones and discuss the exciting perspectives that targeting FEME may boost treatments against cancer and neurodegenerative diseases.

| S-EPMC7319585 | biostudies-literature

Cdk5 and GSK3β inhibit fast endophilin-mediated endocytosis.

Project description:Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Fast Endophilin-mediated endocytosis, FEME, is not constitutively active but triggered upon receptor activation. High levels of growth factors induce spontaneous FEME, which can be suppressed upon serum starvation. This suggested a role for protein kinases in this growth factor receptor-mediated regulation. Using chemical and genetic inhibition, we find that Cdk5 and GSK3β are negative regulators of FEME. They antagonize the binding of Endophilin to Dynamin-1 and to CRMP4, a Plexin A1 adaptor. This control is required for proper axon elongation, branching and growth cone formation in hippocampal neurons. The kinases also block the recruitment of Dynein onto FEME carriers by Bin1. As GSK3β binds to Endophilin, it imposes a local regulation of FEME. Thus, Cdk5 and GSK3β are key regulators of FEME, licensing cells for rapid uptake by the pathway only when their activity is low.

| S-EPMC8065113 | biostudies-literature

SUMOylation of Syntaxin1A regulates presynaptic endocytosis.

Project description:Neurotransmitter release from the presynaptic terminal is under very precise spatial and temporal control. Following neurotransmitter release, synaptic vesicles are recycled by endocytosis and refilled with neurotransmitter. During the exocytosis event leading to release, SNARE proteins provide most of the mechanical force for membrane fusion. Here, we show one of these proteins, Syntaxin1A, is SUMOylated near its C-terminal transmembrane domain in an activity-dependent manner. Preventing SUMOylation of Syntaxin1A reduces its interaction with other SNARE proteins and disrupts the balance of synaptic vesicle endo/exocytosis, resulting in an increase in endocytosis. These results indicate that SUMOylation regulates the emerging role of Syntaxin1A in vesicle endocytosis, which in turn, modulates neurotransmitter release and synaptic function.

| S-EPMC4669484 | biostudies-literature

Cdk5 and GSK3β inhibit fast endophilin-mediated endocytosis

Project description:Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Parallel to Clathrin-mediated endocytosis, additional Clathrin-independent endocytic routes exist, including fast Endophilin-mediated endocytosis (FEME). The latter is not constitutively active but requires the activation of selected receptors. In cell culture, however, the high levels of growth factors in the regular culture media induce spontaneous FEME, which can be suppressed upon serum starvation. Thus, we predicted a role for protein kinases in this growth factor receptor-mediated regulation of the pathway. Using chemical and genetic inhibition, we found that Cdk5 and GSK3β are negative regulators of FEME. Their inhibition was sufficient to activate FEME promptly in resting cells and boosted the production of endocytic carriers containing β 1-adrenergic receptor, following dobutamine addition. We established that the kinases suppress FEME at several levels. They control Dynamin-1 and Dynein recruitment and sorting of cargo receptors such as Plexin A1 and ROBO1 into FEME carriers. They do so by antagonizing the binding of Endophilin to Dynamin-1 as well as to Collapsin response mediator protein 4 (CRMP4), a Plexin A1 adaptor. Cdk5 and GSK3β also hamper the binding and recruitment of Dynein onto FEME carriers by Bin1. Interestingly, we found that GSK3β binds to Endophilin, thus imposing a local regulation of FEME. Collectively, these findings place the two kinases as key regulators of FEME, licensing cells for rapid uptake by the pathway only upon when Cdk5 and GSK3β activity is low.

2021-05-28 | PXD021138 | Pride

Presynaptic mechanisms underlying GABA<sub>B</sub>-receptor-mediated inhibition of spontaneous neurotransmitter release.

Project description:Inhibition of neurotransmitter release by neurotransmitter substances constitutes a fundamental means of neuromodulation. In contrast to well-delineated mechanisms that underlie inhibition of evoked release via suppression of voltage-gated Ca2+ channels, processes that underlie neuromodulatory inhibition of spontaneous release remain unclear. Here, we interrogated inhibition of spontaneous glutamate and GABA release by presynaptic metabotropic GABAB receptors. Our findings show that this inhibition relies on Gβγ subunit action at the membrane, and it is largely independent of presynaptic Ca2+ signaling for both forms of release. In the case of spontaneous glutamate release, inhibition requires Gβγ interaction with the C terminus of the key fusion machinery component SNAP25, and it is modulated by synaptotagmin-1. Inhibition of spontaneous GABA release, on the other hand, is independent of these pathways and likely requires alternative Gβγ targets at the presynaptic terminal.

| S-EPMC8793855 | biostudies-literature

Lactobacillus casei reduces susceptibility to type 2 diabetes via microbiota-mediated body chloride ion influx.

Project description:Gut microbiota mediated low-grade inflammation is involved in the onset of type 2 diabetes (T2DM). In this study, we used a high fat sucrose (HFS) diet-induced pre-insulin resistance and a low dose-STZ HFS rat models to study the effect and mechanism of Lactobacillus casei Zhang in protecting against T2DM onset. Hyperglycemia was favorably suppressed by L. casei Zhang treatment. Moreover, the hyperglycemia was connected with type 1 immune response, high plasma bile acids and urine chloride ion loss. This chloride ion loss was significantly prevented by L. casei via upregulating of chloride ion-dependent genes (ClC1-7, GlyR?1, SLC26A3, SLC26A6, GABAA?1, Bestrophin-3 and CFTR). A shift in the caecal microflora, particularly the reduction of bile acid 7?-dehydroxylating bacteria, and fecal bile acid profiles also occurred. These change coincided with organ chloride influx. Thus, we postulate that the prevention of T2DM onset by L. casei Zhang may be via a microbiota-based bile acid-chloride exchange mechanism.

| S-EPMC4135721 | biostudies-literature

Proton-activated chloride channel PAC regulates endosomal acidification and transferrin receptor-mediated endocytosis.

Project description:During vesicular acidification, chloride (Cl-), as the counterion, provides the electrical shunt for proton pumping by the vacuolar H+ ATPase. Intracellular CLC transporters mediate Cl- influx to the endolysosomes through their 2Cl-/H+ exchange activity. However, whole-endolysosomal patch-clamp recording also revealed a mysterious conductance releasing Cl- from the lumen. It remains unknown whether CLCs or other Cl- channels are responsible for this activity. Here, we show that the newly identified proton-activated Cl- (PAC) channel traffics from the plasma membrane to endosomes via the classical YxxL motif. PAC deletion abolishes the endosomal Cl- conductance, raises luminal Cl- level, lowers luminal pH, and increases transferrin receptor-mediated endocytosis. PAC overexpression generates a large endosomal Cl- current with properties similar to those of endogenous conductance, hypo-acidifies endosomal pH, and reduces transferrin uptake. We propose that the endosomal Cl- PAC channel functions as a low pH sensor and prevents hyper-acidification by releasing Cl- from the lumen.

| S-EPMC7869721 | biostudies-literature

Presynaptic inhibition of GABA(B)-mediated synaptic potentials in the ventral tegmental area during morphine withdrawal.

Project description:Opioids increase the firing of dopamine cells in the ventral tegmental area by presynaptic inhibition of GABA release. This report describes an acute presynaptic inhibition of GABAB-mediated IPSPs by mu- and kappa-opioid receptors and the effects of withdrawal from chronic morphine treatment on the release of GABA at this synapse. In slices taken from morphine-treated guinea pigs after washing out the morphine (withdrawn slices), a low concentration of a mu receptor agonist increased, rather than decreased, the amplitude of the GABAB IPSP. In withdrawn slices, after blocking A1-adenosine receptors with 8-cyclopentyl-1, 3-dipropylxantine, mu-opioid receptor activation inhibited the IPSP at all concentrations and increased the maximal inhibition. In addition, during withdrawal, there was a tonic increase in adenosine tone that was further increased by forskolin or D1-dopamine receptor activation, suggesting that metabolism of cAMP was the source of adenosine. The results indicate that during acute morphine withdrawal, there was an upregulation of the basal level of an opioid-sensitive adenylyl cyclase. Inhibition of this basal activity by opioids had two effects. First, a decrease in the formation of cAMP that decreased adenosine tone. This effect predominated at low mu receptor occupancy and increased the amplitude of the IPSP. Higher agonist concentrations inhibited transmitter release by both kinase-dependent and -independent pathways. This study indicates that the consequences of the morphine-induced upregulation of the cAMP cascade on synaptic transmission are dependent on the makeup of receptors and second messenger pathways present on any given terminal.

| S-EPMC6782572 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data