Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Presynaptic HCN channels regulate vesicular glutamate transport.

ABSTRACT: The amount of neurotransmitter stored in synaptic vesicles determines postsynaptic quantal size and thus the strength of synaptic transmission. However, little is known about regulation of vesicular neurotransmitter uptake. In recordings from the calyx of Held, a giant mammalian glutamatergic synapse, we found that changes in presynaptic Na(+) concentration above and below a resting value of 13 mM regulated vesicular glutamate uptake, consistent with activation of a vesicular monovalent cation Na(+)(K(+))/H(+) exchanger. Na(+) flux through presynaptic plasma membrane hyperpolarization-activated cyclic nucleotide-gated (HCN) channels enhanced presynaptic Na(+) concentration and thus controlled postsynaptic quantal size. Our results indicate that a plasma membrane ion channel controls synaptic strength by modulating vesicular neurotransmitter uptake through a Na(+)-dependent process.

SUBMITTER: Huang H

PROVIDER: S-EPMC4254032 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Presynaptic HCN channels regulate vesicular glutamate transport.

Huang Hai H Trussell Laurence O LO

Neuron 20140925 2

The amount of neurotransmitter stored in synaptic vesicles determines postsynaptic quantal size and thus the strength of synaptic transmission. However, little is known about regulation of vesicular neurotransmitter uptake. In recordings from the calyx of Held, a giant mammalian glutamatergic synapse, we found that changes in presynaptic Na(+) concentration above and below a resting value of 13 mM regulated vesicular glutamate uptake, consistent with activation of a vesicular monovalent cation N ...[more]

PMID: 25263752

Similar Datasets

Presynaptic regulation of quantal size: K+/H+ exchange stimulates vesicular glutamate transport.

Project description:The amount of neurotransmitter stored in a single synaptic vesicle can determine the size of the postsynaptic response, but the factors that regulate vesicle filling are poorly understood. A proton electrochemical gradient (??(H+)) generated by the vacuolar H(+)-ATPase drives the accumulation of classical transmitters into synaptic vesicles. The chemical component of ??(H+) (?pH) has received particular attention for its role in the vesicular transport of cationic transmitters as well as in protein sorting and degradation. Thus, considerable work has addressed the factors that promote ?pH. However, synaptic vesicle uptake of the principal excitatory transmitter glutamate depends on the electrical component of ??(H+) (??). We found that rat brain synaptic vesicles express monovalent cation/H(+) exchange activity that converts ?pH into ??, and that this promotes synaptic vesicle filling with glutamate. Manipulating presynaptic K(+) at a glutamatergic synapse influenced quantal size, indicating that synaptic vesicle K(+)/H(+) exchange regulates glutamate release and synaptic transmission.

| S-EPMC3183113 | biostudies-literature

HCN channels in the hippocampus regulate active coping behavior.

Project description:Active coping is an adaptive stress response that improves outcomes in medical and neuropsychiatric diseases. To date, most research into coping style has focused on neurotransmitter activity and little is known about the intrinsic excitability of neurons in the associated brain regions that facilitate coping. Previous studies have shown that HCN channels regulate neuronal excitability in pyramidal cells and that HCN channel current (Ih ) in the CA1 area increases with chronic mild stress. Reduction of Ih in the CA1 area leads to antidepressant-like behavior, and this region has been implicated in the regulation of coping style. We hypothesized that the antidepressant-like behavior achieved with CA1 knockdown of Ih is accompanied by increases in active coping. In this report, we found that global loss of TRIP8b, a necessary subunit for proper HCN channel localization in pyramidal cells, led to active coping behavior in numerous assays specific to coping style. We next employed a viral strategy using a dominant negative TRIP8b isoform to alter coping behavior by reducing HCN channel expression. This approach led to a robust reduction in Ih in CA1 pyramidal neurons and an increase in active coping. Together, these results establish that changes in HCN channel function in CA1 influences coping style.

| S-EPMC6158061 | biostudies-literature

Presynaptic regulation of quantal size by the vesicular glutamate transporter VGLUT1.

Project description:A fundamental question in synaptic physiology is whether the unitary strength of a synapse can be regulated by presynaptic characteristics and, if so, what those characteristics might be. Here, we characterize a newly proposed mechanism for altering the strength of glutamatergic synapses based on the recently identified vesicular glutamate transporter VGLUT1. We provide direct evidence that filling in isolated synaptic vesicles is subject to a dynamic equilibrium that is determined by both the concentration of available glutamate and the number of vesicular transporters participating in loading. We observe that changing the number of vesicular transporters expressed at hippocampal excitatory synapses results in enhanced evoked and miniature responses and verify biophysically that these changes correspond to an increase in the amount of glutamate released per vesicle into the synaptic cleft. In addition, we find that this modulation of synaptic strength by vesicular transporter expression is endogenously regulated, both across development to coincide with a maturational increase in vesicle cycling and quantal amplitude and by excitatory and inhibitory receptor activation in mature neurons to provide an activity-dependent scaling of quantal size via a presynaptic mechanism. Together, these findings underscore that vesicular transporter expression is used endogenously to directly regulate the extent of glutamate release, providing a concise presynaptic mechanism for controlling the quantal efficacy of excitatory transmission during synaptic refinement and plasticity.

| S-EPMC6725055 | biostudies-literature

Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo.

Project description:Dopamine neurons in the ventral tegmental area (VTA) play an important role in the motivational systems underlying drug addiction, and recent work has suggested that they also release the excitatory neurotransmitter glutamate. To assess a physiological role for glutamate corelease, we disrupted the expression of vesicular glutamate transporter 2 selectively in dopamine neurons. The conditional knockout abolishes glutamate release from midbrain dopamine neurons in culture and severely reduces their excitatory synaptic output in mesoaccumbens slices. Baseline motor behavior is not affected, but stimulation of locomotor activity by cocaine is impaired, apparently through a selective reduction of dopamine stores in the projection of VTA neurons to ventral striatum. Glutamate co-entry promotes monoamine storage by increasing the pH gradient that drives vesicular monoamine transport. Remarkably, low concentrations of glutamate acidify synaptic vesicles more slowly but to a greater extent than equimolar Cl(-), indicating a distinct, presynaptic mechanism to regulate quantal size.

| S-EPMC2846457 | biostudies-literature

Metabolic control of vesicular glutamate transport and release.

Project description:Fasting has been used to control epilepsy since antiquity, but the mechanism of coupling between metabolic state and excitatory neurotransmission remains unknown. Previous work has shown that the vesicular glutamate transporters (VGLUTs) required for exocytotic release of glutamate undergo an unusual form of regulation by Cl(-). Using functional reconstitution of the purified VGLUTs into proteoliposomes, we now show that Cl(-) acts as an allosteric activator, and the ketone bodies that increase with fasting inhibit glutamate release by competing with Cl(-) at the site of allosteric regulation. Consistent with these observations, acetoacetate reduced quantal size at hippocampal synapses and suppresses glutamate release and seizures evoked with 4-aminopyridine in the brain. The results indicate an unsuspected link between metabolic state and excitatory neurotransmission through anion-dependent regulation of VGLUT activity.

| S-EPMC2978156 | biostudies-literature

Protons Regulate Vesicular Glutamate Transporters through an Allosteric Mechanism.

Project description:The quantal nature of synaptic transmission requires a mechanism to transport neurotransmitter into synaptic vesicles without promoting non-vesicular efflux across the plasma membrane. Indeed, the vesicular transport of most classical transmitters involves a mechanism of H(+) exchange, which restricts flux to acidic membranes such as synaptic vesicles. However, vesicular transport of the principal excitatory transmitter glutamate depends primarily on membrane potential, which would drive non-vesicular efflux, and the role of protons is unclear. Adapting electrophysiology to record currents associated with the vesicular glutamate transporters (VGLUTs), we characterize a chloride conductance that is gated by lumenal protons and chloride and supports glutamate uptake. Rather than coupling stoichiometrically to glutamate flux, lumenal protons and chloride allosterically activate vesicular glutamate transport. Gating by protons serves to inhibit what would otherwise be substantial non-vesicular glutamate efflux at the plasma membrane, thereby restricting VGLUT activity to synaptic vesicles.

| S-EPMC4886649 | biostudies-literature

Developmental up-regulation of vesicular glutamate transporter-1 promotes neocortical presynaptic terminal development.

Project description:Presynaptic terminal formation is a complex process that requires assembly of proteins responsible for synaptic transmission at sites of axo-dendritic contact. Accumulation of presynaptic proteins at developing terminals is facilitated by glutamate receptor activation. Glutamate is loaded into synaptic vesicles for release via the vesicular glutamate transporters VGLUT1 and VGLUT2. During postnatal development there is a switch from predominantly VGLUT2 expression to high VGLUT1 and low VGLUT2, raising the question of whether the developmental increase in VGLUT1 is important for presynaptic development. Here, we addressed this question using confocal microscopy and quantitative immunocytochemistry in primary cultures of rat neocortical neurons. First, in order to understand the extent to which the developmental switch from VGLUT2 to VGLUT1 occurs through an increase in VGLUT1 at individual presynaptic terminals or through addition of VGLUT1-positive presynaptic terminals, we examined the spatio-temporal dynamics of VGLUT1 and VGLUT2 expression. Between 5 and 12 days in culture, the percentage of presynaptic terminals that expressed VGLUT1 increased during synapse formation, as did expression of VGLUT1 at individual terminals. A subset of VGLUT1-positive terminals also expressed VGLUT2, which decreased at these terminals. At individual terminals, the increase in VGLUT1 correlated with greater accumulation of other synaptic vesicle proteins, such as synapsin and synaptophysin. When the developmental increase in VGLUT1 was prevented using VGLUT1-shRNA, the density of presynaptic terminals and accumulation of synapsin and synaptophysin at terminals were decreased. Since VGLUT1 knock-down was limited to a small number of neurons, the observed effects were cell-autonomous and independent of changes in overall network activity. These results demonstrate that up-regulation of VGLUT1 is important for development of presynaptic terminals in the cortex.

| S-EPMC3511412 | biostudies-literature

Essential roles of AMPA receptor GluA1 phosphorylation and presynaptic HCN channels in fast-acting antidepressant responses of ketamine.

Project description:Although the molecular mechanism is not clear, the clinically tested drug ketamine has rapid antidepressant action that does not require the multiple weeks of treatment needed for other antidepressant drugs to have an effect. We showed that ketamine potentiated Schaffer collateral-CA1 cell excitatory synaptic transmission in hippocampal slice preparations from rodents and enhanced the phosphorylation of the GluA1 subunit on Ser845 of the AMPA-type glutamate receptor in the hippocampal area CA1. These effects persisted when ?-aminobutyric acid (GABA) receptors were pharmacologically blocked. Ketamine reduced behavioral despair in wild-type mice but had no effect in GluA1 S845A knock-in mutant mice. Presynaptic (CA3 pyramidal cell), but not postsynaptic (CA1 pyramidal cell), deletion of N-methyl-d-aspartate (NMDA)-type glutamate receptors eliminated the ketamine-induced enhancement of excitatory synaptic transmission in hippocampal slices and the antidepressant actions of ketamine in mice. The synaptic and behavioral actions of ketamine were completely occluded by inhibition or deletion of the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1). Our results implicate presynaptic NMDA receptor inhibition followed by reduced activity of presynaptic HCN1 channels, which would result in an increase in glutamate release and postsynaptic glutamate receptor activity, as a mechanism of ketamine action. These data provide a mechanism for changes in synaptic activity that could explain the fast-acting antidepressant effects of this drug.

| S-EPMC5564288 | biostudies-literature

Synaptic SAP97 isoforms regulate AMPA receptor dynamics and access to presynaptic glutamate.

Project description:The synaptic insertion of GluR1-containing AMPA-type glutamate receptors (AMPARs) is critical for synaptic plasticity. However, mechanisms responsible for GluR1 insertion and retention at the synapse are unclear. The synapse-associated protein SAP97 directly binds GluR1 and participates in its forward trafficking from the Golgi network to the plasma membrane. Whether SAP97 also plays a role in scaffolding GluR1 at the postsynaptic membrane is controversial, attributable to its expression as a collection of alternatively spliced isoforms with ill-defined spatial and temporal distributions. In the present study, we have used live imaging and electrophysiology to demonstrate that two postsynaptic, N-terminal isoforms of SAP97 directly modulate the levels, dynamics, and function of synaptic GluR1-containing AMPARs. Specifically, the unique N-terminal domains confer distinct subsynaptic localizations onto SAP97, targeting the palmitoylated alpha-isoform to the postsynaptic density (PSD) and the L27 domain-containing beta-isoform primarily to non-PSD, perisynaptic regions. Consequently, alpha- and betaSAP97 differentially influence the subsynaptic localization and dynamics of AMPARs by creating binding sites for GluR1-containing receptors within their respective subdomains. These results indicate that N-terminal splicing of SAP97 can control synaptic strength by regulating the distribution of AMPARs and, hence, their responsiveness to presynaptically released glutamate.

| S-EPMC3230533 | biostudies-literature

Nanoscale distribution of presynaptic Ca(2+) channels and its impact on vesicular release during development.

Project description:Synaptic efficacy and precision are influenced by the coupling of voltage-gated Ca(2+) channels (VGCCs) to vesicles. But because the topography of VGCCs and their proximity to vesicles is unknown, a quantitative understanding of the determinants of vesicular release at nanometer scale is lacking. To investigate this, we combined freeze-fracture replica immunogold labeling of Cav2.1 channels, local [Ca(2+)] imaging, and patch pipette perfusion of EGTA at the calyx of Held. Between postnatal day 7 and 21, VGCCs formed variable sized clusters and vesicular release became less sensitive to EGTA, whereas fixed Ca(2+) buffer properties remained constant. Experimentally constrained reaction-diffusion simulations suggest that Ca(2+) sensors for vesicular release are located at the perimeter of VGCC clusters (<30 nm) and predict that VGCC number per cluster determines vesicular release probability without altering release time course. This "perimeter release model" provides a unifying framework accounting for developmental changes in both synaptic efficacy and time course.

| S-EPMC4305191 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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