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At least 991 records · Page 55Linked to original sources
PubMed1992

Presynaptic dopamine autoreceptors and second messengers controlling tyrosine hydroxylase activity in rat brain.

In brain areas enriched of dopaminergic nerve terminals presynaptic dopamine (DA) autoreceptors control the state of activation of tyrosine hydroxylase (TH) by regulating the extent of phosphorylation of the enzyme. Evidence is presented indicating that this autoinhibitory control may involve a decrease in the cyclic AMP-dependent activation of TH through an inhibitory coupling of presynaptic DA autoreceptors to adenylate cyclase. As indicated by the insensitivity of the DA inhibition of TH to changes in the extracellular concentrations of Ca++, to the addition of the Ca++ ionophore A 23187 and of different K+ channel blockers, a reduction of Ca++ influx and an increase in the K+ channel activity do not seem to be involved in the presynaptic regulation of TH activity by DA autoreceptors at least under basal conditions.

Animals↗
PubMedDate not supplied

Non-uniform changes in nerve-terminal calcium homeostasis during aging.

Currently unpublished studies indicate reduced rates of calcium clearance from the transmitter release sites in presynaptic terminals of some, but not all, motor nerves in aged rats. Further evidence indicates that deficits in calcium regulation may not necessarily underlie observed age-related changes in evoked transmitter release.

Aging↗
PubMed1991

Target-dependent morphological segregation of Aplysia sensory outgrowth in vitro.

The adult nervous system is characterized by partial or complete morphological segregation of terminals from different afferent neurons innervating the same postsynaptic target. This segregation is thought to result, in part, from competition between the afferent terminals. To explore the role of the target cell in the spatial distribution of presynaptic inputs, the sensory neurons of Aplysia were cultured either with or without a common target motor neuron. In the presence of a common target, the outgrowth from two different sensory neurons tends to occupy separate postsynaptic regions. When cultured without a target motor neuron, processes from different sensory neurons do not segregate, but rather grow freely along one another. Thus, morphological segregation of sensory outgrowth requires interaction with a target neuron and may reflect competition between presynaptic terminals for a limited number of synaptic sites on the motor neuron, or for a postsynaptic trophic factor.

Afferent Pathways↗
PubMed1998

Two sites of action for synapsin domain E in regulating neurotransmitter release.

Synapsins, a family of synaptic vesicle proteins, have been shown to regulate neurotransmitter release; the mechanism(s) by which they act are not fully understood. Here we have studied the role of domain E of synapsins in neurotransmitter release at the squid giant synapse. Two squid synapsin isoforms were cloned and found to contain a carboxy (C)-terminal domain homologous to domain E of the vertebrate a-type synapsin isoforms. Presynaptic injection of a peptide fragment of domain E greatly reduced the number of synaptic vesicles in the periphery of the active zone, and increased the rate and extent of synaptic depression, suggesting that domain E is essential for synapsins to regulate a reserve pool of synaptic vesicles. Domain E peptide had no effect on the number of docked synaptic vesicles, yet reversibly inhibited and slowed the kinetics of neurotransmitter release, indicating a second role for synapsins that is more intimately associated with the release process itself. Thus, synapsin domain E is involved in at least two distinct reactions that are crucial for exocytosis in presynaptic terminals.

Amino Acid Sequence↗
PubMed1976

Presynaptic calcium currents and their relation to synaptic transmission: voltage clamp study in squid giant synapse and theoretical model for the calcium gate.

A voltage clamp study of the presynaptic terminal in squid stellate ganglion has given quantitative results relating inward Ca2+ current to presynaptic membrane potential and postsynaptic response to inward Ca2+ current. The results indicate an S-shaped curve for the relationship between presynaptic potential and Ca2+ current and a linear relationship between Ca2+ current and postsynaptic potential. A similar S-shaped curve was found for the time-dependent properties of the Ca2+ conductance. Based on these results a mathematical model was developed which accounts for the experimental results in this and previously published papers by other authors. The model suggests that five subunits are involved in the Ca2+ gate and that the subunits change noncooperatively from an inactive to an active form upon membrane depolarization.

Animals↗
PubMed1991

Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger.

Although long-term potentiation (LTP) in the CA1 region of the hippocampus is initiated postsynaptically by the influx of Ca2+ through N-methyl-D-aspartate receptor channels, the maintenance of LTP seems to be at least in part presynaptic. This suggests that the postsynaptic cell releases a retrograde messenger to activate the presynaptic terminals. It is likely that this messenger is membrane-permeant and reaches the presynaptic neuron by diffusion. We therefore have investigated two major membrane-permeant candidate retrograde messengers, arachidonic acid and nitric oxide (NO). Consistent with arachidonic acid or a lipoxygenase metabolite being a retrograde messenger, the phospholipase A2 and lipoxygenase inhibitor nordihydroguaiaretic acid blocked LTP in the guinea pig CA1 region in vitro. However, arachidonic acid (up to 100 microM) did not reliably produce activity-independent LTP, and activity-dependent potentiation by arachidonic acid was blocked by DL-aminophosphonovaleric acid. Since nordihydroguaiaretic acid also interferes with signal transduction involving NO, we next examined whether inhibitors of NO synthase block LTP. NG-Nitro-L-arginine blocked LTP when given in the bath, and this inhibition was partially overcome by high concentrations of L-arginine, suggesting that the inhibitor is specific to NO synthase. NG-Nitro-L-arginine and NG-methyl-L-arginine (but not NG-methyl-D-arginine) also blocked LTP when injected intracellularly, indicating that NO synthase is located in the postsynaptic cell. The NO, in turn, seems to be released into the extracellular space, since bathing the slice with hemoglobin, a protein that binds NO and is not taken up by cells, also blocked LTP. Moreover, NO enhances spontaneous presynaptic release of transmitter from hippocampal neurons in dissociated cell culture. These data favor the idea that NO might be a retrograde messenger in LTP.

2-Amino-5-phosphonovalerate↗
PubMed1966

The effect of deprivation of glucose on the ultrastructure and function of the superior cervical ganglion of the rat in vitro.

The superior cervical sympathetic ganglion of the rat kept in vitro in a bicarbonate-buffered Krebs' solution retains its capacity for synaptic transmission and axonal conduction during more than 36 hr. After glucose withdrawal, synaptic transmission is lost in 2(1/2) hr and this loss is irreversible; on the other hand, axonal conduction can still be measured on the postganglionic nerve for more than 24 hr after glucose deprivation. Electrophysiological measurements as well as electron microscope studies revealed specific changes at the level of the presynaptic terminal processes, while the ganglion cells and the satellite cells remained relatively unaltered. The presynaptic lesion due to lack of glucose can be prevented by keeping the preparation in vitro at 6 degrees C. This strongly suggests that this lesion results from a major disturbance of the metabolism of the presynaptic fibers.

Animals↗
PubMed1995

Synaptic alterations in acoustic cortex in Creutzfeldt-Jacob disease.

The acoustic cortex was studied in electron microscope in 10 cases of Creutzfeldt-Jacob disease. The most prominent finding was the tremendous loss of neurons associated with marked reactive astrocytosis. The so called Cajal-Retzius cell had completely disappeared in the first cortical layer. The neuronal synapses were rare and most of those that were preserved demonstrated marked morphological alterations such as extensive dilatation of the synaptic terminals, synaptic polymorphism, dilatation of the cisternae of the smooth endoplasmic reticulum in the presynaptic terminals and accumulation of fibrillary material in the pre- and postsynaptic terminals. Vacuolization and cavity formation were seen in all the cortical layers resulting in an apparent loss of the lamination pattern of the cortex. Hirano bodies and Pick's bodies were seen in some of the neurons in the acoustic cortex. Amyloid plaques were rare in correlation to the other areas of the temporal isocortex of the same material. Correlating the morphological alterations of the neuronal synapses in acoustic cortex with those seen in other areas of the cortex in case of Creutzfeldt-Jacob disease we believe that acoustic cortex is more seriously affected in Creutzfeldt-Jacob disease than most of the other areas of the temporal isocortex.

Amyloid↗
PubMed1982

Secretion of acetylcholine in response to graded depolarization of motor nerve terminals.

1. Depolarizing current pulses were used to elicit transmitter secretion from motor nerve terminals in mouse phrenic nerve-diaphragm preparations exposed to solutions containing tetrodotoxin and 4-aminopyridine. 2. The amplitude of end-plate potentials (e.p.p.s.) elicited by depolarizing pulses was depressed for several milliseconds following a hyperpolarizing pulse, and potentiated following a subthreshold depolarizing pulse. Recovery followed an exponential time-course with time constant of 1.5 to 2.5 ms. 3. The time constant of nerve terminals, calculated from strength-duration curves obtained with depolarizing current pulses that elicited transmitter secretion, ranged from 1.5 to 2.56 ms. 4. It was concluded that the nerve terminal time constant would explain the effects of conditioning polarizations if there were a presynaptic "threshold potential" for end-plate potentials. The decrease in latency of e.p.p.s. as stimulus strength was increased could be explained in the same way. 5. The amplitude of e.p.p.s. increased as depolarizing pulses were lengthened from 2 to 10 ms. When a brief depolarizing pulse was superimposed on a longer subthreshold pulse, e.p.p. amplitude could not be related to the maximum depolarization of the presynaptic terminal. Transmitter secretion appeared to depend on both the level and duration of the depolarization.

Acetylcholine↗
PubMed1995

Synaptic differentiation of a single motor neuron: conjoint definition of transmitter release, presynaptic calcium signals, and ultrastructure.

The opener muscle in the walking legs of the crayfish (Procambarus clarkii) is innervated by only one excitatory motor neuron, yet excitatory postsynaptic potentials (EPSPs) of proximal fibers are eightfold larger than those of central muscle fibers at low frequencies of activation, due in large measure to differences in presynaptic properties. We investigated quantal release properties, calcium signals, and ultrastructure of presynaptic terminals to elucidate factors that could account for the physiological differences. Focal macropatch electrodes were placed over individual visualized terminal varicosities to obtain records of quantal contributions to the excitatory junctional current (EJC). At low frequencies of activation, mean quantal content is greater for proximal than for central varicosities. This difference is due to a higher probability of release per synapse, and not to a larger number of active synapses. Recorded varicosities were labeled with fluorescent beads deposited by the electrode. These beads adhered to the muscle fibers, outlining the recorded site for subsequent serial thin sectioning and reconstruction from electron micrographs. Comparisons of structure and function were made for individual varicosities. The number of active zones per terminal surface area and the number of synapses with multiple active zones (complex synapses) were greater in high-output varicosities. Calcium indicators were loaded into proximal and central nerve terminals by axonal injection to compare the relative differences in calcium buildup during stimulation. Presynaptic calcium signals were larger for proximal varicosities than for central varicosities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Differential turnover of tubulin and neurofilament proteins in central nervous system neuron terminals.

The transport of tubulin and neurofilament protein subunits from the preterminal axons of guinea pig retinal ganglion cells into their presynaptic terminals in the superior colliculus was examined. Newly synthesized tubulin and neurofilament proteins were radiolabeled with tritiated amino acids in the cell bodies and were allowed to be axonally transported through the optic axons and into the terminals in the superior colliculi. Superior colliculi were harvested at appropriate times, synaptosomes were prepared, and radiolabeled proteins were examined by gel electrophoresis and fluorography. Proteins in the radiolabeled synaptosomes were compared with those in the portion of the optic tract immediately proximal to the superior colliculus. Tubulin subunits entered the terminals by 100 days after intraocular labeling, and at least one isoform of tubulin appeared to persist as long as 400 days. Neurofilament proteins, despite the fact that they are axonally transported and delivered to the terminals in concert with the tubulin subunits, disappear rapidly upon entry into the terminals themselves.

Animals↗
PubMed1991

Alien intracellular calcium chelators attenuate neurotransmitter release at the squid giant synapse.

A number of calcium buffers were examined for their ability to reduce evoked transmitter release when injected into the presynaptic terminal of the squid giant synapse. Injection of EGTA was virtually ineffective at reducing transmitter release, even at estimated intracellular concentrations up to 80 mM. Conversely, the buffer 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), which has an equilibrium affinity for calcium similar to that of EGTA at pH 7.2, produced a substantial reduction in transmitter release when injected presynaptically. This effect of BAPTA was reversible, presumably because the buffer diffused out of the terminal and into uninjected regions of the presynaptic axon. BAPTA derivatives with estimated intracellular calcium dissociation constants (Kd) ranging from 0.18 to 4.9 microM were effective at reducing transmitter release at similar estimated concentrations. A BAPTA derivative with an estimated intracellular Kd of 31 mM was less effective. BAPTA did not affect presynaptic action potentials or calcium spikes in ways that could explain its ability to reduce transmitter release. The relative effects of presynaptic injections of BAPTA and derivatives are consistent with the calcium-buffering capability of these compounds if the presynaptic calcium transient that triggers release is hundreds of microM or larger. The superior potency of BAPTA compared to EGTA apparently results from the faster calcium-binding kinetics of BAPTA and suggests that the calcium-binding molecule that triggers release binds calcium in considerably less than 200 microsec and is located very close to calcium channels.

Animals↗
PubMed2002

Differential expression of neuronal calcium sensor-1 in the developing chick retina.

Neuronal calcium sensor-1 (NCS-1) is a Ca(2+) binding protein that has been implicated in the regulation of neurotransmission and synaptogenesis. In this study we investigated the developmental expression and localization of NCS-1 in the chick retina. Single- and double-labeling experiments with three-dimensional reconstruction as well as ultrastructural data of the distribution of NCS-1 suggest that this protein is also involved in axonal process outgrowth. We found an early expression of NCS-1 in ganglion cells and their axons, in amacrine, and in horizontal cells, whereas photoreceptors were immunonegative at embryonic stages. In the early posthatching days we found strong immunostaining for NCS-1 in horizontal cells and their processes in the outer plexiform layer. In contrast, synaptic vesicle protein 2 (SV2) was prominent only in photoreceptor synaptic terminals. Ultrastructural analysis confirmed that NCS-1 was localized postsynaptically in horizontal cell processes, whereas presynaptic terminals were immunonegative. However, at late posthatching days we observed that photoreceptor ribbon synapses (from rods and/or cones) also expressed NCS-1. Thus the results support the notion that NCS-1 is involved in neuronal process outgrowth and is localized in pre- and postsynaptic compartments including mature photoreceptor synapses.

Animals↗
PubMed2006

Purinergic transmission in the central nervous system.

The adenosine 5'-triphosphate (ATP), discovered in 1929 by Karl Lohman, Cyrus Hartwell Fiske, and Yellagaprada SubbaRow, acts as an important extracellular signaling molecule. In the CNS, ATP can be released from synaptic terminals, either on its own or together with other neurotransmitters. After the release from the presynaptic terminals, ATP binds to a plethora of ionotropic and metabotropic receptors, which mediate its action as an excitatory neurotransmitter. Furthermore, ATP also acts as an important mediator in neuronal-glial communications because glial cells are endowed with numerous ATP receptors, which trigger Ca(2+) signaling events and membrane currents in both macro and microglia. In addition, ATP can be released from astroglial cells, thereby acting as a mediator of glial-glial and glial-neuronal signaling.

Adenosine↗
PubMed1991

The amino terminus of the putative Drosophila choline acetyltransferase precursor is cleaved to yield the 67 kDa enzyme.

A putative precursor of the 67 kDa choline acetyltransferase (Acetyl-CoA: choline-O-acetyltransferase; EC 2.3.1.6) polypeptide from Drosophila was examined using polyclonal antibodies. The central purpose of the study was to probe the suspected precursor with anti-peptide antibodies that could identify a cleavable amino terminal domain, since such a structure could be responsible for targeting the enzyme to the presynaptic terminal. Antisera were produced to both a plasmid-expressed fusion-free enzyme protein and a 26-amino acid-long peptide reproducing sequence from the enzyme. Both antisera were capable of precipitating enzyme activity from crude supernatants. Western blotting with the antibody to the plasmid-expressed enzyme visualized a major polypeptide at 75 kDa and minor polypeptides at 67 and 54 kDa. Affinity-purified IgG to the synthetic peptide only recognized the 75 kDa component and was unable to recognize purified 67 kDa enzyme protein. Timed autolysis of the enzyme in crude homogenates demonstrated both a 67 kDa polypeptide that was present prior to homogenization and a species that appeared as a product of the autolysis. The evidence from this study is consistent with the expectation that the 75 kDa band, visualized on Western blots with antisera to the enzyme, is an authentic enzyme protein. These data further suggested that the 75 kDa protein is an amino-terminally extended precursor of the 67 kDa enzyme that can be cleaved to generate the 67 kDa species.

Amino Acid Sequence↗
PubMed1998

Inactivation of presynaptic calcium current contributes to synaptic depression at a fast central synapse.

Voltage-gated calcium channels are well characterized at neuronal somata but less thoroughly understood at the presynaptic terminal where they trigger transmitter release. In order to elucidate how the intrinsic properties of presynaptic calcium channels influence synaptic function, we have made direct recordings of the presynaptic calcium current (I(pCa)) in a brainstem giant synapse called the calyx of Held. The current was pharmacologically classified as P-type and exhibited marked inactivation. The inactivation was largely dependent upon the inward calcium current magnitude rather than the membrane potential, displayed little selectivity between divalent charge carriers (Ca2+, Ba2+ and Sr+), and exhibited slow recovery. Simultaneous pre- and postsynaptic whole-cell recording revealed that I(pCa) inactivation predominantly contributes to posttetanic depression of EPSCs. Thus, because of its slow recovery, I(pCa) inactivation underlies this short-term synaptic plasticity.

Animals↗
PubMed1996

Visualization of D1 dopamine receptors on living nucleus accumbens neurons and their colocalization with D2 receptors.

To examine the substrate for dopamine (DA) synaptic action in the nucleus accumbens (nAcc), we visualized the cellular and subcellular distribution of DA receptors on postnatal nAcc neurons in culture using fluoroprobe derivatives of DA receptor ligands. Previously, we have shown that rhodamine-N-(p-aminophenethyl)-spiperone (NAPS) (10 nM), a derivative of the D2 antagonist spiperone, labels D2-like receptors on living nAcc neurons. We now show that rhodamine-Sch-23390 (30 nM), a derivative of the D1 antagonist, labels D1-like receptors. Putative specific membrane labeling reached a plateau after about 20 min. Labeling was stereospecific, as it was unaffected by competition with (-)-butaclamol, but blocked with (+)-butaclamol. We found that 52 +/- 7% of nAcc medium-sized neurons showed D1 labeling, which extended onto the dendrites. Labeling was also seen on presynaptic terminals, often abutting D1-positive and D1-negative cell bodies, consistent with a presynaptic modulatory role for D1 receptors. Larger neurons, which may be GABAergic or cholinergic interneurons, were also labeled. By sequential labeling first with rhodamine-Sch-23390 and then rhodamine-NAPS, we found that 38 +/- 6% of medium-sized neurons express both D1- and D2-like receptors, indicating that D1-D2 interactions may occur at the level of single postsynaptic neurons.

Animals↗
PubMed2000

Effect of a memory-enhancing drug, AIT-082, on the level of synaptophysin.

Our objective is to study the effect of AIT-082 on the level of synaptophysin in cultured pheochromocytoma (PC12) cells. The drug AIT-082, a unique purine hypoxanthine derivative, is under development for the treatment of Alzheimer's disease (AD). We analyzed synaptophysin protein as an index of synaptic numbers and density and indirectly neuronal transmission. PC12 cells were treated with nerve growth factor (NGF) (50 ng/ml) and/or different doses of AIT-082 (5-50 ng/ml) obtained from NeoTherapeutics, CA. In the western immunoblots of conditioned media and cell lysates, we detected synaptophysin as 36-40 kDa protein bands. When PC12 cells were treated with NGF and samples were analyzed at 24 or 48 hours after treatment, the secretion of synaptophysin was drastically reduced in the conditioned medium. A significant reduction in the intracellular levels of synaptophysin in NGF-treated samples was also noted. By contrast, when PC12 cells were treated with AIT-082, the secretion of synaptophysin was increased in the conditioned medium as compared to the control. There was also a significant increase in the intracellular levels of synaptophysin in AIT-082-treated cultures. NGF treatment resulted in sympathetic neuronal phenotypes in PC12 cells. As it is known that the immunoreactivity of the synaptophysin protein correlates with the density of the synaptic terminal, our results suggest that treatment by AIT-082 could enhance neurotransmitter release at the presynaptic terminal, which may play a role in the improvement of cognition seen in AD subjects.

Adrenal Gland Neoplasms↗