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PubMed2003

p53 is present in synapses where it mediates mitochondrial dysfunction and synaptic degeneration in response to DNA damage, and oxidative and excitotoxic insults.

A form of programmed cell-death called apoptosis occurs in neurons during development of the nervous system, and may also occur in a variety of neuropathological conditions. Here we present evidence obtained in studies of adult mice and neuronal cell cultures showing that p53 protein is present in synapses where its level and amount of phosphorylation are increased following exposure of the cells to the DNA-damaging agent etoposide. We also show that levels of active p53 increase in isolated cortical synaptosomes exposed to oxidative and excitotoxic insults. Increased levels of p53 also precede loss of synapsin I immunoreactive terminals in cultured hippocampal neurons exposed to etoposide. Synaptosomes from p53-deficient mice exhibit increased resistance to oxidative and excitotoxic insults as indicated by stabilization of mitochondrial membrane potential and decreased production of reactive oxygen species. Finally, we show that a synthetic inhibitor of p53 (PFT-alpha) protects synaptosomes from wild-type mice against oxidative and excitotoxic injuries, and preserves presynaptic terminals in cultured hippocampal neurons exposed to etoposide. Collectively, these findings provide the first evidence for a local transcription-independent action of p53 in synapses, and suggest that such a local action of p53 may contribute to the dysfunction and degeneration of synapses that occurs in various neurodegenerative disorders.

Animals↗
PubMed2002

Activation of presynaptic P2X7-like receptors depresses mossy fiber-CA3 synaptic transmission through p38 mitogen-activated protein kinase.

P2X(7) receptor subunits form homomeric ATP-gated, calcium-permeable cation channels. In this study, we used Western blots and immunocytochemistry to demonstrate that P2X(7) receptors are abundant on presynaptic terminals of mossy fiber synapses in the rat hippocampus. P2X(7)-immunoreactive protein was detected using a specific P2X(7) antibody in Western blots of protein isolated from whole hippocampus and from a subcellular fraction containing mossy fiber synaptosomes. P2X(7) immunoreactivity was colocalized with syntaxin 1A/B-immunoreactivity in mossy fiber terminals in the dentate hilus and stratum lucidum of CA3. Extracellular and whole-cell voltage-clamp recordings in CA3 revealed that bath application of the potent P2X(7) agonist 2',3'-O-(4-benzoylbenzoyl)-ATP (Bz-ATP) caused a long-lasting inhibition of neurotransmission at mossy fiber-CA3 synapses. Consistent with a presynaptic action at mossy fiber synapses, Bz-ATP had no significant effect on neurotransmission at associational-commissural synapses in CA3 but increased paired-pulse facilitation during depression of mossy fiber evoked currents. In addition, Bz-ATP had no postsynaptic effect on holding current or conductance of CA3 neurons. Bz-ATP-induced mossy fiber synaptic depression was blocked by the P2X(7) antagonist oxidized ATP but not by the P2X(1-3,5,6) antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid or the P2Y antagonist reactive blue 2. Finally, an antagonist of p38 MAP kinase activation [4-(4-fluorophenyl)2-(4-methylsulfinylphenyl)5-(4-pyridyl)imidazole] but not extracellular signal-regulated kinase 1/2 MAP kinase (2'-amino-3'-methoxyflavone) blocked the synaptic depression mediated by Bz-ATP, suggesting that this presynaptic inhibition was mediated by activation of p38 MAP kinase. The results of the present study demonstrate that activation of presynaptic P2X(7) receptors depresses mossy fiber-CA3 synaptic transmission through activation of p38 MAP kinase.

Adenosine↗
PubMed2000

A conserved clathrin assembly motif essential for synaptic vesicle endocytosis.

Although clathrin assembly by adaptor proteins (APs) plays a major role in the recycling of synaptic vesicles, the molecular mechanism that allows APs to assemble clathrin is poorly understood. Here we demonstrate that AP180, like AP-2 and AP-3, binds to the N-terminal domain of clathrin. Sequence analysis reveals a motif, containing the sequence DLL, that exists in multiple copies in many clathrin APs. Progressive deletion of these motifs caused a gradual reduction in the ability of AP180 to assemble clathrin in vitro. Peptides from AP180 or AP-2 containing this motif also competitively inhibited clathrin assembly by either protein. Microinjection of these peptides into squid giant presynaptic terminals reversibly blocked synaptic transmission and inhibited synaptic vesicle endocytosis by preventing coated pit formation at the plasma membrane. These results indicate that the DLL motif confers clathrin assembly properties to AP180 and AP-2 and, perhaps, to other APs. We propose that APs promote clathrin assembly by cross-linking clathrin triskelia via multivalent interactions between repeated DLL motifs in the APs and complementary binding sites on the N-terminal domain of clathrin. These results reveal the structural basis for clathrin assembly and provide novel insights into the molecular mechanism of clathrin-mediated synaptic vesicle endocytosis.

Adaptor Protein Complex alpha Subunits↗
PubMed2002

Regulation of retrograde signaling at neuromuscular junctions by the novel C2 domain protein AEX-1.

Retrograde signaling from postsynaptic cells to presynaptic neurons is essential for regulation of synaptic development, maintenance, and plasticity. Here we report that the novel protein AEX-1 controls retrograde signaling at neuromuscular junctions in C. elegans. aex-1 mutants show neural defects including reduced presynaptic activity and abnormal localization of the synaptic vesicle fusion protein UNC-13. Muscle-specific AEX-1 expression rescues these defects but neuron-specific expression does not. AEX-1 has an UNC-13 homologous domain and appears to regulate exocytosis in muscles. This retrograde signaling requires prohormone-convertase function in muscles, suggesting that a peptide is the retrograde signal. This signal regulates synaptic vesicle release via the EGL-30 Gq(alpha) protein at presynaptic terminals.

Amino Acid Sequence↗
PubMed2000

Endogenous regulators of G protein signaling proteins regulate presynaptic inhibition at rat hippocampal synapses.

Presynaptic inhibition mediated by G protein-coupled receptors (GPCRs) can develop and decay in a few seconds. This time course is too rapid to be accounted for by the intrinsic GTPase activity of Galpha subunits alone. Here, we test the hypothesis that endogenous regulators of G protein signaling (RGS proteins) are required for rapid, brief presynaptic inhibition. Endogenous G protein alpha subunits were uncoupled from GPCRs by treating cultures with pertussis toxin (PTX). Adenoviral expression of mutant PTX-insensitive (PTX-i) Galpha(i1-3) or Galpha(o) subunits rescued adenosine-induced presynaptic inhibition in cultured hippocampal neurons. Expression of double mutant Galpha(i1) or Galpha(o) subunits that were both PTX-insensitive and unable to bind RGS proteins (PTX/RGS-i) also rescued presynaptic inhibition. Presynaptic inhibition mediated by PTX/RGS-i subunits decayed much more slowly after agonist removal than that mediated by PTX-i subunits or native G proteins. The onset of presynaptic inhibition mediated by PTX/RGS-i Galpha(o) was also slower than that mediated by PTX-i Galpha(o). In contrast, the onset of presynaptic inhibition mediated by PTX/RGS-i Galpha(i1) was similar to that mediated by PTX-i Galpha(i1). These results suggest that endogenous RGS proteins regulate the time course of G protein signaling in mammalian central nervous system presynaptic terminals.

Adenoviridae↗
PubMed1997

[The ultrastructure of the synapses in the upper layers of the cat cerebral cortex after applying strychnine].

Ultrastructure of axo-dendritic and axo-spinous synapses in upper layers of cat brain gyrus suprasylvii was studied in 10, 30 and 90 min application of 0.1% strychnine nitrate and also 2.5 and 5 hrs after 90 min long use of strychnine. Portion of active synaptic contacts was found to grow higher in 10 and 30 min application and smaller during and 2.5 hrs after 90 min application. However, synaptic vesicles number is sharply reduced beginning from min 30 of application and only on 5th postapplication hr reaches initial level. Application of strychnine does not cause changes in synapse active zone length and presynaptic terminals section area. Reorganisations in pre- and postsynaptic terminals most acutely manifested in 90 min application are reversible--on 5th postapplication hr synapse ultrastructure turns into similar to that of control material.

Animals↗
PubMed2002

Short-term retrograde inhibition of GABAergic synaptic currents in rat Purkinje cells is mediated by endogenous cannabinoids.

Depolarization-induced suppression of inhibition (DSI) is a form of short-term plasticity of GABAergic synaptic transmission that is found in cerebellar Purkinje cells and hippocampal CA1 pyramidal cells. DSI involves the release of a calcium-dependent retrograde messenger by the somatodendritic compartment of the postsynaptic cell. Both glutamate and endogenous cannabinoids have been proposed as retrograde messenger. Here we show that, in cerebellar parasagittal slices, type 1 cannabinoid receptors (CB1Rs) are expressed at high levels in axons of GABAergic interneurons and in presynaptic terminals onto Purkinje cells. Application of the cannabinoid antagonist AM-251 (500 nm) leads to the abolition of the DSI of evoked currents (eIPSCs) recorded in paired recordings and to a strong reduction of the DSI of TTX-insensitive miniature events (mIPSCs) recorded from Purkinje cells. Furthermore, the CB1R agonist WIN 55-212,2 (5 microm) induces a presynaptic inhibition of synaptic currents similar to that occurring during DSI, as well as an occlusion of DSI after stimulation of Purkinje cells. Moreover, WIN 55-212,2 reduces the calcium transients evoked in presumed presynaptic varicosities by short trains of action potentials. Our results indicate that DSI is mediated by the activation of presynaptic CB1Rs and that an endogenous cannabinoid is a likely candidate retrograde messenger in this preparation. They further suggest that DSI involves distinct presynaptic modifications for eIPSCs and mIPSCs, including an inhibition of action potential-evoked calcium rises.

Action Potentials↗
PubMed1994

Cyclothiazide unmasks AMPA-evoked stimulation of [3H]-L-glutamate release from rat hippocampal synaptosomes.

The effect of alpha-amino-3-hydroxy-5-methylisoxazolepropionate (AMPA) on Ca(2+)-sensitive, tetrodotoxin (TTX)-insensitive K(+)-stimulated [3H]-L-glutamate release from rat hippocampal synaptosomes was determined. AMPA in the presence, but not in the absence of cyclothiazide, a drug which blocks AMPA receptor desensitization, elicited a dose-dependent increase in K(+)-stimulated [3H]-L-glutamate release but had no effect on basal release. The AMPA/cyclothiazide stimulation was blocked by CNQX and by GYKI 52466, an antagonist at the cyclothiazide site. These results indicate that AMPA receptors are present on presynaptic terminals and suggest that they may play a role in the regulation of neurotransmitter release.

Animals↗
PubMed1995

Effects of an indene-derivative, TN-871, on synaptic transmission in a sympathetic ganglion: presynaptic actions on neurotransmitter release.

Intracellular recordings were made from bullfrog sympathetic ganglion cells to elucidate effects of 2-n-butyl-1-(4-methylpiperazinyl)-5,6-methylenedioxyindene.2 HCl (TN-871) on synaptic transmission. TN-871 at 30 nM augmented cholinergic nicotinic fast excitatory postsynaptic potentials (fast EPSPs), whereas the drug at 3 microM reversibly depressed them, without affecting acetylcholine-induced depolarizations. TN-871 did not affect active and passive electrical properties of the ganglion cells. The quantal analysis method was applied to the fast EPSPs in a 0.54 mM Ca2+/7.56 mM Mg2+ Ringer's solution. The mean quantal content was significantly increased by TN-871 at 30 nM but significantly decreased at 3 microM. TN-871 at 300 nM either increased or decreased the mean quantal content. The mean quantal size of the fast EPSPs was not changed by TN-871 at the concentrations examined. Fast EPSPs in a 0.99 mM Ca2+/4.86 mM Mg2+ Ringer's solution were not affected by nicardipine, but were inhibited in amplitude by omega-conotoxin in a concentration-dependent manner. It is likely that TN-871, in high concentrations, might block omega-conotoxin-sensitive N-type calcium channels in the presynaptic terminals. These results indicate that TN-871 modulates transmitter release from preganglionic nerve terminals without changing the postsynaptic sensitivity of the ganglion cells to ACh.

Animals↗
PubMed2001

Activation of presynaptic group III metabotropic glutamate receptors depresses spontaneous inhibition in layer V of the rat entorhinal cortex.

Whole cell voltage clamp recording was used to investigate neurotransmitter release onto neurones in deep and superficial layers of rat entorhinal cortex in vitro. Activation of metabotropic glutamate receptors with the agonist (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid depressed spontaneous release of the inhibitory neurotransmitter GABA in layer V, but not in layer II. Depression of transmitter release did not persist in the presence of the sodium channel blocker tetrodotoxin. It seems likely that activation of presynaptic glutamate heteroreceptors inhibits action potential dependent release of neurotransmitter via a direct action at the presynaptic terminal. We confirmed that depression of inhibitory neurotransmission in layer V was mediated by group III metabotropic glutamate receptors using a specific group III antagonist, (RS)-cyclopropyl-4-phosphonophenylglycine. Application of the antagonist alone did not alter the frequency of spontaneous neurotransmitter release, suggesting that the metabotropic glutamate receptor is not tonically active. In layer V of the entorhinal cortex, activation of presynaptic metabotropic glutamate receptors enhances spontaneous glutamate release, and inhibits spontaneous release of GABA. These effects may combine to increase random action potential firing in this layer, thereby reducing its capacity for synchrony generation. Our results are consistent with an anticonvulsant action for group III metabotropic glutamate receptors in the entorhinal cortex.

Animals↗
PubMed2002

Intracellular ionic concentration by calibration from fluorescence indicator emission spectra, its relationship to the K(d), F(min), F(max) formula, and use with Na-Green for presynaptic sodium.

The emission spectra calibration curves for a fluorescence indicator and the F(min), F(max), and K(d) formula were shown to be related. Using the known calibrated fluorescence emitted by Sodium Green (Na-Green) and photo-multiplier-tube quantum efficiency, we calculated the detection signal over a range of sodium concentrations. The calculated calibration curves were compared for optical filters passing a narrow band, medium band or full spectrum. We found that a method based on the full emission spectrum was the most appropriate. Given a known resting concentration of intracellular sodium, calibrated readings can be converted to concentration values. This method is applicable to any fluorescence indicator when curves for emission spectra over a range of concentrations are available. We measured sodium concentration changes during trains of action potentials (APs) at a crayfish motor axon's presynaptic terminals injected with Na-Green. During low frequency AP trains, net sodium increases asymptotically with frequency. Average net Na-flux per AP decreases for increasing terminal size. The terminals of crayfish motor axon have surface area to volume ratio which is 7700 times larger than for squid. Thus, in comparison to squid, crayfish terminals exhibit a larger change in [Na(+)](i) during equivalent AP activity.

Action Potentials↗
PubMed2002

Intrinsic determinants of synaptic phenotype: an experimental study of abducens internuclear neurons connecting with anomalous targets.

The present experiments investigate the role of postsynaptic neurons in the morphological differentiation of presynaptic terminals that are formed de novo in the adult CNS. Abducens internuclear neurons in the adult cat were chosen as the experimental model. These neurons project onto the contralateral medial rectus motoneurons of the oculomotor nucleus. Abducens internuclear axon terminals were identified by their anterograde labeling with biocytin and analyzed at the electron microscopic level. To promote the formation of new synapses, two different experimental approaches were used. First, after the selective ablation of medial rectus motoneurons with ricin, abducens internuclear neurons reinnervated the neighboring oculomotor internuclear neurons. Second, after axotomy followed by embryonic cerebellar grafting, abducens internuclear axons invaded the implanted tissue and established synaptic connections in both the molecular and granule cell layer. Boutons contacting the oculomotor internuclear neurons developed ultrastructural characteristics that resembled the control synapses on medial rectus motoneurons. In the grafted cerebellar tissue, abducens internuclear axons and terminals did not resemble climbing or mossy fibers but showed similarities with control boutons. However, labeled boutons analyzed in the granule cell layer established a higher number of synaptic contacts than controls. This could reflect a trend towards the mossy fiber phenotype, although labeled boutons significantly differed in every measured parameter with the mossy fiber rosettes found in the graft. We conclude that at least for the abducens internuclear neurons, the ultrastructural differentiation of axon terminals reinnervating novel targets in the adult brain seems to be mainly under intrinsic control, with little influence by postsynaptic cells.

Abducens Nerve↗
PubMed1994

Electron-microscopic investigations of vasoactive intestinal peptide (VIP)-like immunoreactive terminal formations in the lateral septum of the pigeon.

Vasoactive intestinal peptide (VIP)-like immunoreactive terminal fields were examined in the lateral septum of the pigeon by means of immunocytochemistry. According to light-microscopic observations, these projections originated from VIP-like immunoreactive cerebrospinal fluid (CSF)-contacting neurons, which are located in the ependymal layer of the lateral septum and form a part of the lateral septal organ. The processes of these cells gave rise to dense terminal-like structures in the lateral septum. Pre-embedding immuno-electron microscopy revealed that VIP-like immunoreactive axon terminals had synaptoid contacts with perikarya of small VIP-immunonegative neurons of the lateral septum, which were characterized by an invaginated nucleus, numerous mitochondria, a well-developed Golgi apparatus, endoplasmic reticulum and a small number of dense-core vesicles (about 100 nm in diameter). VIP-like immunoreactive axons were also seen in contact with immunonegative dendrites in the lateral septum. In both axosomatic and axodendritic connections, VIP-like immunoreactive presynaptic terminals contained large dense-core vesicles, clusters of small vesicles and mitochondria. These findings suggest that VIP-immunoreactive neurons of the lateral septal organ project to small, presumably peptidergic nerve cells of the lateral septum and that the VIP-like neuropeptide serves as a neuromodulator (-transmitter) in this area.

Animals↗
PubMed2002

Brain-derived neurotrophic factor modulates cerebellar plasticity and synaptic ultrastructure.

Neurotrophins are key regulators of neuronal survival and function. Here we show that TrkB, the receptor for brain-derived neurotrophic factor (BDNF), is located at parallel fiber to Purkinje cell (PF/PC) synapses of the cerebellum. To determine the effects of TrkB receptor activation on synapse formation and function, we examined the parallel fiber to Purkinje cell synapses of mice with a targeted deletion of the BDNF gene. Although Purkinje cell dendrites are abnormal in BDNF -/- mice, PF/PC synapses are still able to form. Immunohistochemical analysis of mutant animals revealed the formation of numerous PF/PC synapses with the appropriate apposition of presynaptic and postsynaptic proteins. These synapses are functional, and no differences were detected in the waveform of evoked EPSCs, the amplitude of spontaneous mini-EPSCs, or the response to prolonged 10 Hz stimulus trains. However, paired-pulse facilitation, a form of short-term plasticity, is significantly decreased in BDNF -/- mice. Detailed ultrastructural analysis of the presynaptic terminals demonstrated that this change in synaptic function is accompanied by an increase in the total number of synaptic vesicles in mutant mice and a decrease in the proportion of vesicles that are docked. These data suggest that BDNF regulates both the mechanisms that underlie short-term synaptic plasticity and the steady-state relationship between different vesicle pools within the terminal.

Animals↗
PubMed2003

[Modulation of extracellular calcium on miniature inhibitory postsynaptic currents of Xenopus' optic tectal neurons].

Experiments were performed to study the relationship between presynaptic calcium and miniature inhibitory postsynaptic currents (mIPSCs) using voltage-clamp technique with whole cell mode in Xenopus optic tectal slices. The results are as follows: The frequency of mIPSCs decreased from 1.91+/-0.59 Hz to 0.34+/-0.09 Hz in calcium-free solution (paired t test, P=0.019, n=8), the value of mIPSCs frequency being (25.5+/-4.4)% of control. In order to rule out the effect of remaining calcium in perfusing solution we further applied calcium-free solution containing egtazic acid, ethyleneglycol-bis (beta-aminoethylether)-N,N -tetraacetic acid (EGTA) (200 nmol/L-2 mmol/L). The mIPSCs frequency changed from 1.57+/-0.57 in control to 0.89+/-0.41 Hz in calcium-free solution containing EGTA (paired t test, P=0.002, n=12), decreasing to (40.0+/-5.9)% of control. There is no statistical difference in the results between Ca(2+)-free perfusion and Ca(2+)-free solution containing EGTA (paired t test, P=0.74, n=9). When cadmium chloride (CdCl2, 100 micromol/L), a non-specific Ca(2+) channel blocker, was applied to the bath solution, the mIPSCs frequency decreased from 1.15+/-0.34 Hz in control to 0.25+/-0.09 Hz in CdCl2-containing solution (paired t test, P=0.008, n=11), reaching (29.25+/-6.1)% of control. However, the amplitude did not change much. An endoplasmic reticulum pump inhibitor thapsigargin increased the mIPSCs frequency from 0.93+/-0.19 Hz to 1.58+/-0.28 Hz (paired t test, P=0.002, n=11). The value in the latter is (214.6 +/-49.1)% of that in the former. In order to exclude the remaining calcium from the bathing solution, the mIPSCs frequency was first recorded from calcium-free solution as control (0.41+/-0.08 Hz) and then from calcium-free containing TG solution (8-16 micromol/L)(0.71+/-0.15 Hz)(paired t test, P=0.026, n=5), increasing to (175.0+/-14.6)% of control. The endoplasmic reticulum Ca(2+) store RyR agonist (ryanodine, 10-100 nmol/L) enhanced mIPSCs frequency from 1.18+/-0.40 Hz to 1.80+/-0.44 Hz with increment of (261.8+/-89.5)% (paired t test, P=0.004, n=6). However, the endoplasmic reticulum RyR antagonist (procaine, 2 mmol/L) could inhibit mIPSCs from 1.26+/-0.35 Hz to 0.43+/-0.15 Hz (paired t test, P=0.027, n=6). U73122 (40 micromol/L), a phosphalipase C inhibitor, decreased also mIPSCs frequency from 2.01+/-0.58 Hz in control to 0.92+/-0.40 Hz in U73122-containing solution (paired t test, P=0.002, n=10). Caffeine (10 mmol/L) markedly diminished mIPSCs frequency from 3.22+/-0.64 Hz to 0.15+/-0.30 Hz (paired t test, P=0.003, n=7), which is (4.6+/-2.9)% compared to control. Furthermore, in some cases the caffeine could abolish mIPSCs. Taken together, our results demonstrated that cytosolic calcium might be important for mediating the generation of mIPSCs. The cytosolic calcium could be increased by calcium influx through membrane calcium channel on presynaptic membrane, and/or by calcium released through RyR and IP(3)R in presynaptical internal store. The increased cytosolic Ca(2+) both from external solution or internal Ca(2+) stores might increase the transmitter vesicles at the presynaptic terminal, which in turn results in the increase of the mIPSCs frequency in the postsynaptic neurons.

Animals↗
PubMed2001

The neurobiology of slow synaptic transmission.

Nerve cells communicate with each other through two mechanisms, referred to as fast and slow synaptic transmission. Fast-acting neurotransmitters, e.g., glutamate (excitatory) and gamma-aminobutyric acid (GABA) (inhibitory), achieve effects on their target cells within one millisecond by virtue of opening ligand-operated ion channels. In contrast, all of the effects of the biogenic amine and peptide neurotransmitters, as well as many of the effects of glutamate and GABA, are achieved over hundreds of milliseconds to minutes by slow synaptic transmission. This latter process is mediated through an enormously more complicated sequence of biochemical steps, involving second messengers, protein kinases, and protein phosphatases. Slow-acting neurotransmitters control the efficacy of fast synaptic transmission by regulating the efficiency of neurotransmitter release from presynaptic terminals and by regulating the efficiency with which fast-acting neurotransmitters produce their effects on postsynaptic receptors.

Adenylyl Cyclases↗
PubMed2001

Opposing changes in phosphorylation of specific sites in synapsin I during Ca2+-dependent glutamate release in isolated nerve terminals.

Synapsins are major neuronal phosphoproteins involved in regulation of neurotransmitter release. Synapsins are well established targets for multiple protein kinases within the nerve terminal, yet little is known about dephosphorylation processes involved in regulation of synapsin function. Here, we observed a reciprocal relationship in the phosphorylation-dephosphorylation of the established phosphorylation sites on synapsin I. We demonstrate that, in vitro, phosphorylation sites 1, 2, and 3 of synapsin I (P-site 1 phosphorylated by cAMP-dependent protein kinase; P-sites 2 and 3 phosphorylated by Ca(2+)-calmodulin-dependent protein kinase II) were excellent substrates for protein phosphatase 2A, whereas P-sites 4, 5, and 6 (phosphorylated by mitogen-activated protein kinase) were efficiently dephosphorylated only by Ca(2+)-calmodulin-dependent protein phosphatase 2B-calcineurin. In isolated nerve terminals, rapid changes in synapsin I phosphorylation were observed after Ca(2+) entry, namely, a Ca(2+)-dependent phosphorylation of P-sites 1, 2, and 3 and a Ca(2+)-dependent dephosphorylation of P-sites 4, 5, and 6. Inhibition of calcineurin activity by cyclosporin A resulted in a complete block of Ca(2+)-dependent dephosphorylation of P-sites 4, 5, and 6 and correlated with a prominent increase in ionomycin-evoked glutamate release. These two opposing, rapid, Ca(2+)-dependent processes may play a crucial role in the modulation of synaptic vesicle trafficking within the presynaptic terminal.

4-Aminopyridine↗
PubMed1990

Activation of mu- and delta-opioid receptors present on the same nerve terminals depresses transmitter release in the mouse hypogastric ganglion.

1. The inhibitory actions of mu- and delta-opioid receptor agonists on the strong, single fibre synaptic input to neurones contained in the mouse hypogastric ganglion have been examined. 2. The opioid agonists [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAMGO, 10 nM-10 microM), morphine (10-30 [D-Ser2,Leu5,Thr6]enkephalin (DSLET, 3 nM-1 microM), [D-Pen2,D-Pen5]enkephalin (DPDPE, 10 nM-10 microM), all depressed the single fibre, all-or-nothing, nicotinic, excitatory synaptic potential (e.p.s.p.) recorded in mouse hypogastric ganglion neurones. U50488H (0.3-1 microM) was without effect. 3. The effect of DSLET, but not that of DAMGO, was reversed by the delta-opioid receptor-selective antagonist, ICI 174864 (0.3 microM). Naloxone (0.3 microM) antagonized the effect of both DSLET and DAMGO. 4. The site of action of the mu- and delta-receptor agonists was on the presynaptic terminals, since at the concentrations which depressed the e.p.s.p. these drugs did not affect the resting membrane potential or input resistance of the postganglionic neurone body, nor did they depress the postganglionic, nicotinic response to exogenously applied acetylcholine. 5. Quantal analysis further confirmed the presynaptic site of action; mu- and delta-opioid receptor agonists decreased the mean number of quanta released per stimulus but did not reduce the mean amplitude of the quantal unit. 6. It was concluded that mu- and delta-opioid receptors were located on the same presynaptic nerve terminals since, in the same neurones, mu- and delta-opioid receptor agonists depressed the same single fibre inputs. 7. The potassium channel blockers barium and quinine, at concentrations known to block opioidactivated somatic potassium conductances, reduced slightly but did not abolish the mu- and delta-opioid receptor-mediated inhibition of the e.p.s.p.

Animals↗