Regulation of acetylcholinesterase activity by nitric oxide in rat neuromuscular junction via N -methyl- d -aspartate receptor activation (original) (raw)
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Glutamate regulation of non-quantal release of acetylcholine in the rat neuromuscular junction
Journal of Neurochemistry, 2003
Glutamate, previously demonstrated to participate in regulation of the resting membrane potential in skeletal muscles, also regulates non-quantal acetylcholine (ACh) secretion from rat motor nerve endings. Non-quantal ACh secretion was estimated by the amplitude of endplate hyperpolarization (H-effect) following blockade of skeletal muscle post-synaptic nicotinic receptors by (+)-tubocurarine and cholinesterase by armin (diethoxy-p-nitrophenyl phosphate). Glutamate was shown to inhibit non-quantal release but not spontaneous and evoked quantal secretion of ACh. Glutamate-induced decrease of the H-effect was enhanced by glycine. Glycine alone also lowered the H-effect, probably due to potentiation of the effect of endogenous glutamate present in the synaptic cleft. Inhibition of N-methyl-D-aspartate (NMDA) receptors with (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10imine (MK801), DL-2-amino-5-phosphopentanoic acid (AP5) and 7-chlorokynurenic acid or the elimination of Ca 2+ from the bathing solution prevented the glutamate-induced decrease of the H-effect with or without glycine. Inhibition of muscle nitric oxide synthase by N G -nitro-L-arginine methyl ester (L-NAME), soluble guanylyl cyclase by 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and binding and inactivation of extracellular nitric oxide (NO) by haemoglobin removed the action of glutamate and glycine on the H-effect. The results suggest that glutamate, acting on post-synaptic NMDA receptors to induce sarcoplasmic synthesis and release of NO, selectively inhibits non-quantal secretion of ACh from motor nerve terminals. Non-quantal ACh is known to modulate the resting membrane potential of muscle membrane via control of activity of chloride transport and a decrease in secretion of nonquantal transmitter following muscle denervation triggers the early post-denervation depolarization of muscle fibres. Abbreviations used: ACh, acetylcholine; AP5, DL-2-amino-5-phosphopentanoic acid; D-NAME, N G -nitro-D-arginine methyl ester; EPP, endplate potentials; L-NAME, N G -nitro-L-arginine methyl ester; mEPP, miniature endplate potentials; MK801, (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine; NO, nitric oxide; ODQ, 1H[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one.
Differential regulation of neocortical synapses by neuromodulators and activity
Neuron, 1997
the thalamus into the cortex, and intracortical (IC) synapses mediate the flow and recombination of informa-* Department of Physiology Zlotowski Center for Neuroscience tion within the cortex. Neocortical neurons and synapses are regulated by several diffuse ascending Ben-Gurion University Beer-Sheva 84105 modulatory systems, whose activity varies sharply during changes in behavioral state and sleep-wake cycles Israel † Department of Neuroscience . The dynamic regulation of these synapses by activity Brown University Providence, Rhode Island 02912 and modulators may be important for perception, memory, and changes in behavioral state (Hasselmo, 1995; Fisher et al., 1997). Virtually nothing is known about the specificity of neuromodulators for different types of Summary synapses in the neocortex. Here, we show that afferent (TC) synapses and associational (IC) synapses of neo-Synapses are continually regulated by chemical moducortex have distinct short-term dynamics that are differlators and by their own activity. We tested the specificentially regulated by neuromodulators. ity of regulation in two excitatory pathways of the neocortex: thalamocortical (TC) synapses, which mediate specific inputs, and intracortical (IC) synapses, which Results mediate the recombination of cortical information.
Regulation of efficacy at central synapses
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1984
The quantal nature of synaptic depression produced by high frequency stimulations has been analyzed at a central synapse for the first time. Simultaneous intracellular recordings were obtained from the Mauthner cell and adjacent identifiable inhibitory interneurons. The presynaptic cells were stimulated at frequencies from 2 to 33 Hz, and the corresponding release parameters were determined using a computational procedure described elsewhere (Korn, H., A. Triller, A. Mallet, and D. S. Faber (1981) Science 213: 898-901). As in our previous studies, these entities were correlated with histological features of the neurons following systematic horseradish peroxidase injections and reconstructions. Evidence was obtained that, in the range of physiological conditions used, the binomial parameter n (number of available quanta for release) remains constant; thus every synaptic bouton continues to function as an independent all-or-none releasing unit. The progressive reduction in amplitude o...
Neuroscience and behavioral physiology
Experiments on rat diaphragm muscles showed that glutamate (10 microM-1 mM) had no effect on the mean frequency, interspike intervals, and amplitude-time characteristics of miniature endplate potentials, but had a suppressive action on non-quantum secretion (the intensity of which was assessed in terms of the H effect). The effect of glutamate was markedly concentration-dependent and was completely overcome by blockade of NMDA receptors, inhibition of NO synthase, and by binding of NO molecules in the extracellular space by hemoglobin. It is suggested that glutamate can modulate the non-quantum release of acetylcholine, initiating the synthesis of NO molecules in muscle fibers via activation of NMDA receptors followed by the retrograde action of NO on nerve terminals.
Journal of Neurochemistry, 2005
N-Acetylaspartylglutamate (NAAG), known to be present in rat motor neurons, may participate in neuronal modulation of nonquantal secretion of acetylcholine (ACh) from motor nerve terminals. Non-quantal release of ACh was estimated by the amplitude of the endplate membrane hyperpolarization (H-effect) caused by inhibition of nicotinic receptors by (+)-tubocurarine and acetylcholinesterase by armin (diethoxyp-nitrophenyl phosphate). Application of exogenous NAAG decreased the H-effect in a dose-dependent manner. The reduction of the H-effect by NAAG was completely removed when N-acetyl-b-aspartylglutamate (bNAAG) or 2-(phosphonomethyl)-pentanedioic acid (2-PMPA) was used to inhibit glutamate carboxypeptidase II (GCP II), a presynaptic Schwann cell membrane-associated ectoenzyme that hydrolyzes NAAG to glutamate and N-acetylaspartate. Bath application of glutamate decreased the H-effect similarly to the action of NAAG but N-acetylaspartate was without effect.
Journal of Neuroscience, 2006
In this study, we investigated the mechanisms underlying synaptic plasticity at the layer IV to II/III pathway in barrel cortex of mice aged 6 -13 weeks. This pathway is one of the likely candidates for expression of experience-dependent plasticity in the barrel cortex and may serve as a model for other IV to II/III synapses in the neocortex. We found that postsynaptic autocamtide-2-inhibitory peptide is sufficient to block long-term potentiation (LTP) (IC 50 of 500 nM), implicating postsynaptic calcium/calmodulin-dependent kinase II in LTP induction. AMPA receptor subunit 1 (GluR1) knock-out mice also showed LTP in this pathway, but potentiation was predominantly presynaptic in origin as determined by paired-pulse analysis, coefficient of variation analysis, and quantal analysis, whereas wild types showed a mixed presynaptic and postsynaptic locus. Quantal analysis at this synapse was validated by measuring uniquantal events in the presence of strontium. The predominantly presynaptic LTP in the GluR1 knock-outs was blocked by postsynaptic antagonism of nitric oxide synthase (NOS), either with intracellular N--nitro-L-arginine methyl ester or N-nitro-L-arginine, providing the first evidence for a retrograde transmitter role for NO at this synapse. Antagonism of NOS in wild types significantly reduced but did not eliminate LTP (group average reduction of 50%). The residual LTP formed a variable proportion of the total LTP in each cell and was found to be postsynaptic in origin. We found no evidence for silent synapses in this pathway at this age. Finally, application of NO via a donor induced potentiation in layer II/III cells and caused an increase in frequency but not amplitude of miniature EPSPs, again implicating NO in presynaptic plasticity.
Molecular Brain Research, 2001
In brain synapses, nitric oxide synthase activation is coupled to N-methyl-D-aspartate-mediated calcium entry at postsynaptic densities through regulatory protein complexes, however a presynaptic equivalent to this signaling mechanism has not yet been identified. Novel evidence indicates that N-methyl-D-aspartate glutamate receptors may play a presynaptic role in synaptic plasticity. Thus, we investigated whether ionotropic glutamate receptor activation in isolated nerve terminals regulates neurotransmitter release, through nitric oxide formation. N-Methyl-D-aspartate dose-dependently inhibited the release of glutamate evoked by 4-aminopyridine (IC 5155 mM), and 50 this effect was reversed by the N-methyl-D-aspartate receptor antagonist D-(2)-2-amino-5-phosphopentanoic acid and by the nitric oxide synthase inhibitor, L-nitroarginine, in synaptosomes isolated from whole hippocampus, CA3 and CA1 areas, but not from the dentate gyrus. In contrast, the 4-aminopyridine-evoked release of glutamate was reduced by a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or kainate by a nitric oxide-independent mechanism, since it was not blocked by L-nitroarginine, and N-methyl-D-aspartate, but not a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or kainate, significantly increased cGMP formation. Presynaptic N-methyl-Daspartate receptors are probably involved since removing extracellular nitric oxide with the scavenger 2-(4-carboxyphenyl)-4,4,5,5tetramethylimidazoline-1-oxyl 3-oxide did not block the depression of glutamate release by N-methyl-D-aspartate. The mechanism underlying this depression involves the inhibition of synaptic vesicle exocytosis since N-methyl-D-aspartate / nitric oxide inhibited the 3 1 4 release of [ H]glutamate and [ C]GABA evoked by hypertonic sucrose. The results also suggest that presynaptic N-methyl-D-aspartate receptors may function as auto-and heteroreceptors.
Reaction mechanism determines NMDA receptor response to repetitive stimulation
Nature, 2004
At central excitatory synapses, N-methyl-D-aspartate (NMDA) receptors, which have a high affinity for glutamate 1 , produce a slowly rising synaptic current in response to a single transmitter pulse and an additional current after a second, closely timed stimulus 2. Here we show, by examining the kinetics of transmitter binding and channel gating in single-channel currents from recombinant NR1/NR2A receptors, that the synaptic response to trains of impulses is determined by the molecular reaction mechanism of the receptor. The rate constants estimated for the activation reaction predict that, after binding neurotransmitter, receptors hesitate for ,4 ms in a closed high-affinity conformation before they either proceed towards opening or release neurotransmitter, with about equal probabilities. Because only about half of the initially fully occupied receptors become active, repetitive stimulation elicits currents with distinct waveforms depending on pulse frequency. This high-affinity/lowefficiency activation mechanism might serve as a link between stimulation frequency and the directionality of the ensuing synaptic plasticity. Given the high affinity of NMDA receptors (NRs) for glutamate estimated from macroscopic current dose-response profiles (equilibrium dissociation constant K d , 3 mM) 1,3 and the estimated high glutamate concentration in the cleft after the release of a single synaptic vesicle (1-5 mM) 4,5 , it was widely believed that the NR glutamate-binding sites become saturated after each synaptic vesicle release 6. This assumption has been called into question by studies indicating that the synaptic glutamate transient might be lower and shorter than previously thought 7 and by evidence that at some central excitatory synapses a single release event does not elicit a maximal NR current response 2,8-11. Macroscopic current measurements give estimates of apparent affinity that depend inextricably on the gating properties of the channel, whereas single-channel kinetic analyses permit ligand binding and conformational transitions to be determined separately. To estimate the glutamate association and dissociation rate constants, and hence their ratio, K d , we recorded single-channel currents from cell-attached patches of HEK293 cells transiently expressing rat NR1 and NR2A subunits under experimental conditions that preclude the occupancy of extraneous receptor states such as those resulting from cation binding in the pore 12 or at allosteric extracellular sites on the receptor 13,14. Activity was elicited by steady-state saturating concentrations of glycine (100 mM) plus several concentrations of glutamate (20 nM to 2 mM). As reported previously for saturation conditions 15,16 , individual NRs generated three patterns of activity ('modes') at all glutamate concentrations tested (Fig. 1). We classified periods with homogenous gating kinetics according to channels' mean open times (MOTs), namely high (H, ,33 ms), medium (M, ,11 ms) or low (L, ,3.7 ms) (Supplementary Table S1). Similar results were obtained with several concentrations (0.1-100 mM) of the co-agonist glycine in the presence of 1 mM glutamate (data not shown). A channel's MOT tended to decrease in discrete steps with recording time, as
Activity-Dependent Modulation of Synaptic AMPA Receptor Accumulation
Neuron, 1998
atory synaptic transmission in cultured spinal neurons * Howard Hughes Medical Institute results in an increase in the glutamate chemosensitivity † Department of Neuroscience of the postsynaptic neuron (O'Brien and Fischbach, ‡ Department of Neurology 1986). Segal and Furshpan reported that this same Johns Hopkins University School of Medicine blockade resulted in large excitatory synaptic potentials Baltimore, Maryland 21205 and epileptic discharges in cultured hippocampal neu-§ Department of Neuroscience rons (1990). Recently, Turrigiano et al. (1998) have re-Harvard Medical School ported that blocking excitatory synaptic transmission in Boston, Massachusetts 02110 cortical neurons results in increased mEPSC amplitudes and increased postsynaptic glutamate sensitivity. Postsynaptic ionotropic glutamate receptors are composed Summary of three broad classes, termed AMPA, NMDA, and kainate type receptors, on the basis of molecular and phar-Both theoretical and experimental work have sugmacological criteria (Hollmann and Heinemann, 1994). gested that central neurons compensate for changes The predominant charge carrier during routine fast excitin excitatory synaptic input in order to maintain a relaatory synaptic transmission is the AMPA type receptor, tively constant output. We report here that inhibition while NMDA receptors contribute a significant calcium current, which is thought to modulate second messenof excitatory synaptic transmission in cultured spinal ger systems and kinases. To date, experiments have neurons leads to an increase in mEPSC amplitudes, suggested that the increased mEPSC amplitude and accompanied by an equivalent increase in the accuneuronal glutamate sensitivity resulting from the blockmulation of AMPA receptors at synapses. Conversely, ade of excitatory synaptic activity are due to an alterincreasing excitatory synaptic activity leads to a deation in the AMPA class of receptors (O'Brien and Fischcrease in synaptic AMPA receptors and a decline in bach, 1986; Turrigiano et al., 1998), although one recent mEPSC amplitude. The time course of this synaptic report also noted an effect on NMDA receptor distriburemodeling is slow, similar to the metabolic half-life tion (Rao and Craig, 1997). Whether the activity-reguof neuronal AMPA receptors. Moreover, inhibiting exlated increase in postsynaptic glutamate sensitivity recitatory synaptic transmission significantly prolongs sults from a change in the number of postsynaptic AMPA the half-life of the AMPA receptor subunit GluR1, sugreceptor subunits or from a change in their single changesting that synaptic activity modulates the size of nel properties is unclear. Precedents for both mechathe mEPSC by regulating the turnover of postsynaptic nisms exist. Recent work on inhibitory synapses in the AMPA receptors. cerebellum has suggested that postsynaptic GABA A receptor number can determine quantal size (Nusser et