Neurotransmitter uptake: a tool in identifying neurotransmitter-specific pathways.
Explore the source record for details and available documents.
Acetylcholine↗
SEARCH · Search PubMed
Results for “Neurotransmitters”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Changes in the status of neurotransmitter receptors in a rabbit model of hepatic encephalopathy.
It has previously been shown in an animal model of hepatic encephalopathy (HE) that the number of receptors for the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), increases and that the number of receptors for the excitatory neurotransmitter, glutamate, decreases. To determine the functional status of other neurotransmitter systems in HE, measurements were made of the specific binding of other neurotransmitters to synaptic membranes prepared from the brains of normal rabbits and rabbits in HE due to galactosamine-induced acute liver failure. The development of HE was associated with: (i) a decrease in the density (Bmax) of receptors for the two excitatory amino acid neurotransmitters, aspartate and kainic acid; (ii) an increase in the Bmax of both the low and high affinity binding site for strychnine, a marker for the inhibitory neurotransmitter glycine; (iii) a decrease in the affinity (Kd) of receptors for dopamine, and (iv) no appreciable change in either the specific binding of [3H]D-ala2-methionine enkephalinamide or [3H]naloxone, markers for opiate receptors, or in the Bmax or the Kd of receptors for acetylcholine. If it is assumed that the sensitivity of the brain to neurotransmitters varies directly with the density of neurotransmitter receptors, HE may be associated with increased sensitivity to inhibitory amino acid neurotransmitters and decreased sensitivity to excitatory amino acid neurotransmitters. Thus, the observed changes in neurotransmitter receptors in HE afford a feasible pathophysiological basis for the mediation of the neural inhibition of HE.
Animals↗
Neurotransmitters in the regulation of neuronal cytoarchitecture.
Recent experiments in isolated neurons in cell culture have demonstrated that neurotransmitters and associated electrical activity can directly affect neurite outgrowth. The results indicate that neurotransmitters have considerable potential to control the development of the neuronal circuits in which they participate in information coding in the adult. Cellular mechanisms regulating growth cone motility have been found to be similar to those regulating neurotransmitter release at the synapse and involve electrical activity, calcium and other second messengers. These similarities suggest that the morphological changes in connections observed in adult plasticity may involve the transition of synaptic terminals back to a growth mode. Excitatory and inhibitory neurotransmitters can interact to yield a net effect on neuronal morphology. In the intact nervous system a balance between these neurotransmitter inputs is probably important in maintaining circuits. Studies of neurotransmitter involvement in learning and memory processes indicate that brain function can alter brain structure and that neurotransmitters may control these structural changes. The hippocampus is one brain region in which we are beginning to define roles for neurotransmitters as sculptors of neuronal cytoarchitecture. The neurotransmitter glutamate was found to specifically affect the cytoarchitecture of hippocampal pyramidal neuron dendrites in a graded manner which suggests that glutamate may be involved in: establishing hippocampal circuitry during brain development; maintaining and modifying circuitry in the adult; and inducing neurodegeneration in several disorders including epilepsy, Alzheimer's disease, and stroke. Therapeutic approaches to disorders which affect brain cytoarchitecture may now be devised based upon knowledge of the neurotransmitters and their cellular mechanisms in the pertinent brain region.
Animals↗
Nitric oxide and peroxynitrite as factors to stimulate neurotransmitter release in the CNS.
This review summarizes the stimulatory potentials of NO and peroxynitrite (OONO-) on neurotransmitter release in the central nervous system. Exogenous and endogenous NO stimulates to release neurotransmitter. NO synthesized intracellularly diffuses out through neuronal membrane and acts on the outer side of membrane to depolarize neuronal membrane, which triggers neurotransmitter release. NO-induced release of neurotransmitters is mediated by Ca2+-dependent and -independent processes. The latter process is operated by reverse process of the Na+-dependent carrier-mediated neurotransmitter uptake system or by unknown mechanisms. Ca2+-dependent release of neurotransmitter occurs in part subsequent to increase in Ca2+ influx via VDCCs, although N-type VDCCs may not involve in this action of NO because of suppression of Ca2+ influx through N-type VDCCs by NO. Participation of cGMP formation by NO on neurotransmitter release is controversial. A superoxide scavenger, Ca2+, Zn(2+)-superoxide dismutase, abolishes NO-induced neurotransmitter release and synthesized OONO- induces neurotransmitter release, indicating that OONO- participates in NO-evoked neurotransmitter release.
Animals↗
Abnormal neurotransmitter release underlying behavioral and cognitive disorders: toward concepts of dynamic and function-specific dysregulation.
Abnormalities in the regulation of neurotransmitter release and/or abnormal levels of extracellular neurotransmitter concentrations have remained core components of hypotheses on the neuronal foundations of behavioral and cognitive disorders and the symptoms of neuropsychiatric and neurodegenerative disorders. Furthermore, therapeutic drugs for the treatment of these disorders have been developed and categorized largely on the basis of their effects on neurotransmitter release and resulting receptor stimulation. This perspective stresses the theoretical and practical implications of hypotheses that address the dynamic nature of neurotransmitter dysregulation, including the multiple feedback mechanisms regulating synaptic processes, phasic and tonic components of neurotransmission, compartmentalized release, differentiation between dysregulation of basal vs activated release, and abnormal release from neuronal systems recruited by behavioral and cognitive activity. Several examples illustrate that the nature of the neurotransmitter dysregulation in animal models, including the direction of drug effects on neurotransmitter release, depends fundamentally on the state of activity of the neurotransmitter system of interest and on the behavioral and cognitive functions recruiting these systems. Evidence from evolving techniques for the measurement of neurotransmitter release at high spatial and temporal resolution is likely to advance hypotheses describing the pivotal role of neurotransmitter dysfunction in the development of essential symptoms of major neuropsychiatric disorders, and also to refine neuropharmacological mechanisms to serve as targets for new treatment approaches. The significance and usefulness of hypotheses concerning the abnormal regulation of the release of extracellular concentrations of primary messengers depend on the effective integration of emerging concepts describing the dynamic, compartmentalized, and activity-dependent characteristics of dysregulated neurotransmitter systems.
Animals↗
Development of neurotransmitter metabolism in embryos of the leech Haementeria ghilianii.
We have investigated the development of neurotransmitter metabolism in embryos of the glossiphoniid leech Haementeria ghilianii. The neurotransmitter content of dissected embryonic tissues was measured by means of radioenzymatic assays, while the presence of neurotransmitters in individual identified neurons was detected by means of immunocytochemical and monoamine histofluorescence techniques. The capacity for synthesis of neurotransmitters was measured by incubating dissected embryonic tissues in radiolabeled neurotransmitter precursors. A specific neurotransmitter uptake system present in some neurons was detected by means of an autoradiographic technique. At an early stage of development of the nervous system, when most neurons are just beginning process outgrowth, the nerve cord acquires the capacity to synthesize ACh, 5-HT, and GABA from their immediate precursors, and contains ACh. Moreover, 5-HT-immunoreactive neurons and neurons that are capable of GABA uptake can be identified. Dopamine-containing neurons are first detected by their histofluorescence at a slightly later stage, after process outgrowth is under way. As development continues, the content of and capacity for synthesis of these neurotransmitters increase, as does the number of neurons capable of GABA uptake. During the earlier stages of development, ACh content exceeds 5-HT content, which in turn exceeds dopamine content. By the end of embryogenesis, however, 5-HT and dopamine contents have greatly increased relative to ACh content, with 5-HT content exceeding ACh content by a factor of 2. Of the neurotransmitters thus far studied, 5-HT is present in the highest amount in the juvenile and adult nerve cord. Our results indicate that in the development of the leech nervous system neurotransmitter metabolism is one of the first neuronal characters to differentiate and that the subsequent levels of the different neurotransmitters are differentially regulated.
Acetylcholine↗
Prenatal exposure to drugs of abuse in humans: effects on placental neurotransmitter receptors.
Recently, the concept of behavioral teratology has evolved. In animal models, prenatal exposure to low doses of psychotropics (e.g., methadone, diazepam) results in abnormal development of behavior. Furthermore, in animals, pre- and perinatal exposure to psychoactive drugs results in altered brain neurochemistry. In humans, similar behavioral and neurological disruptions have been reported. The mechanisms responsible for these effects are unknown; however, all of these psychotropics have high affinity, specific interactions with various neurotransmitter receptors. Furthermore, normal development of nervous tissue appears to be mediated through neurotransmitter receptors. Disruption of normal, receptor-mediated "signals" by psychoactive agents would be expected to alter development of brain. In order to examine the regulation of neurotransmitter receptors by centrally acting agents, we have compared placental neurotransmitter receptors from "control" and substance-abusing women, hypothesizing that (1) placental neurotransmitter receptor regulation may mirror fetal brain neurotransmitter receptor regulation and (2) placental neurotransmitter receptors themselves may play a role in development. Standard radioligand binding methods were employed. Control values were relatively consistent while substance-abusing values were inconsistent, with wide variation in each substance-abusing group, possibly indicative of "regulation" of neurotransmitter receptors, yet certainly complicated by other variables surrounding gestation and birth (e.g., drug dosage and schedule, length of labor). In this regard, levels of neurotransmitter receptors were consistently higher (20-100%) in caesarian section tissue, possibly reflecting "down-regulation" of neurotransmitter receptors in placentas by the known excess sympathetic and opiate activity during labor.(ABSTRACT TRUNCATED AT 250 WORDS)
Female↗
Role of calcium in neurotransmitter release evoked by alpha-latrotoxin or hypertonic sucrose.
At the synapse, neurotransmitter release is triggered physiologically by Ca(2+) influx through voltage-gated Ca(2+) channels. Non-physiologically, release can be evoked by a potent neurotoxin, alpha-latrotoxin, and by hypertonic sucrose. Controversy has arisen on whether release evoked by alpha-latrotoxin and hypertonic sucrose requires extracellular Ca(2+) or Ca(2+) from intracellular stores. Using synaptosomes, we have studied the Ca(2+) dependence of alpha-latrotoxin and sucrose action in different neurotransmitter systems. In agreement with previous data, no requirement for extracellular Ca(2+) in sucrose-induced secretion of norepinephrine, dopamine, glutamate or GABA was detected. Unexpectedly, we observed large differences between these neurotransmitters in the Ca(2+) dependence of alpha-latrotoxin-stimulated release: norepinephrine release required Ca(2+), dopamine release was only partially Ca(2+) dependent, and glutamate and GABA release did not require Ca(2+). To test if Ca(2+) derived from intracellular Ca(2+) stores participates in neurotransmitter release triggered by alpha-latrotoxin or hypertonic sucrose, we employed thapsigargin, a Ca(2+)-ATPase inhibitor that empties Ca(2+) stores. Thapsigargin did not induce neurotransmitter release, nor did it inhibit subsequent release stimulated by KCl depolarization, hypertonic sucrose or alpha-latrotoxin. However, intracellular Ca(2+) performs an important regulatory function, since thapsigargin increased the size of the readily releasable pool as measured by stimulation with hypertonic sucrose. This effect required extracellular Ca(2+) and protein kinase C, suggesting that depletion of internal Ca(2+) stores leads to store-operated Ca(2+) entry. The resulting Ca(2+) influx does not trigger release by itself, but activates protein kinase C that increases the readily releasable pool of neurotransmitters. Our data show that internal and external Ca(2+) is not acutely involved in hypertonic sucrose-evoked neurotransmitter release, while alpha-latrotoxin-triggered release requires external Ca(2+) for a subset of neurotransmitters. Although internal Ca(2+) is not essential for release, it modulates its extent, implying that the emptying of intracellular stores by activation of presynaptic receptors plays an important regulatory role in neurotransmitter release.
Animals↗
Prenatal and postnatal contents of amino acid neurotransmitters in mouse parietal cortex.
This study documents the variation in the amino acid neurotransmitter contents during mouse parietal cortex development, from embryonic day 13 (E13) until young adulthood, between postnatal day 21 (P21) and P30. Taurine, an inhibitory neurotransmitter and neuromodulator, is the most abundant neurotransmitter in the developing neocortex, whereas, at the adult stage, glutamate is the more prominent neurotransmitter playing an excitatory role, and GABA is the major inhibitory neurotransmitter. During the proliferative stage of neurogenesis in the mouse cerebral cortex, between E13 and E17, relatively high levels of glutamate, aspartate, taurine and glycine were detected, consistent with a possible trophic influence of these neurotransmitters during cortical development prior to synaptogenesis. Between E17 and E19, a significant decline in the contents of these neurotransmitters was observed, consistent with earlier reports of cell death in the ventricular and subventricular zones during this stage of development. During the perinatal period, a progressive increment in glutamate level was seen between E21 and P5, and then the values remained constant until the second postnatal week. Glutamate also decreased by about 25% between P11 and P15, on the other hand, aspartate diminished by about 20% between P7 and P9. These results were consistent with previous reports of histogenetic cell death during the first 2 postnatal weeks in mouse neocortex. GABA increased from the embryonic period until young adulthood, in contrast, the glycine content decreased; thus, in the adult parietal cortex, the GABA content was about 2.6-fold higher than that of glycine. During the first postnatal week, the concentrations of glutamate and GABA showed significant increments between P0 and P5, while those of aspartate and glycine remained constant. During this period, amino acids are predominantly excitatory and the cerebral cortex is vulnerable to epileptiform activity; the significant increment in taurine content between P0 and P3 suggests a neuroprotective action of taurine against excitotoxicity. At P15, coinciding with the period of maximum cortical synaptogenesis, significant increments in GABA and glycine contents were observed which could be related to the maturation of inhibitory synaptic transmission. At the young adult stage, there was a rise in the levels of both excitatory neurotransmitters, glutamate and aspartate, and a significant reduction in the contents of all three inhibitory neurotransmitters, GABA, glycine and taurine.
Animals↗
Receptor-mediated regulation of calcium channels and neurotransmitter release.
Ca2+ influx into the nerve terminal is normally the trigger for the release of neurotransmitters. Many neurons possess presynaptic receptors whose activation results in changes in the quantity of neurotransmitter released by an action potential. This paper reviews studies that show that presynaptic receptors can regulate the activity of Ca2+ channels in the nerve terminal, resulting in changes in the influx of Ca2+ and in neurotransmitter release. Neurons possess several different types of voltage-sensitive Ca2+ channels. Ca2+ influx through N-type channels appears to trigger transmitter release in many instances. In other cases Ca2+ influx through L channels can influence transmitter release. Neurotransmitters can inhibit N channels through a G protein-mediated transduction mechanism. The G proteins are frequently pertussis toxin substrates. Inhibition of N channels appears to involve changes in their voltage dependence. Neurotransmitters can also regulate neuronal K+ channels. Activation of these K+ channels can lead to a reduction in Ca2+ influx and neurotransmitter release; these effects are also mediated by G proteins. Thus neurotransmitters may often regulate both presynaptic Ca2+ and K+ channels. These two effects may be synergistic mechanisms for the regulation of Ca2+ influx and neurotransmitter release.
Animals↗
Astrocytic neurotransmitter receptors in situ and in vivo.
In the brain, astrocytes are associated intimately with neurons and surround synapses. Due to their close proximity to synaptic clefts, astrocytes are in a prime location for receiving synaptic information from released neurotransmitters. Cultured astrocytes express a wide range of neurotransmitter receptors, but do astrocytes in vivo also express neurotransmitter receptors and, if so, are the receptors activated by synaptically released neurotransmitters? In recent years, considerable efforts has gone into addressing these issues. The experimental results of this effort have been compiled and are presented in this review. Although there are many different receptors which have not been identified on astrocytes in situ, it is clear that astrocytes in situ express a number of different receptors. There is evidence of glutamatergic, GABAergic, adrenergic, purinergic, serotonergic, muscarinic, and peptidergic receptors on protoplasmic, fibrous, or specialized (Bergmann glia, pituicytes, Müller glia) astrocytes in situ and in vivo. These receptors are functionally coupled to changes in membrane potential or to intracellular signaling pathways such as activation of phospholipase C or adenylate cyclase. The expression of neurotransmitter receptors by astrocytes in situ exhibits regional and intraregional heterogeneity and changes during development and in response to injury. There is also evidence that receptors on astrocytes in situ can be activated by neurotransmitter(s) released from synaptic terminals. Given the evidence of extra-synaptic signaling and the expression of neurotransmitter receptors by astrocytes in situ, direct communication between neurons and astrocytes via neurotransmitters could be a widespread form of communication in the brain which may affect many different aspects of brain function, such as glutamate uptake and the modulation of extracellular space.
Animals↗
Neurotransmitters and neuromodulators during early human development.
BACKGROUND: Neurotransmitters such as monoamines appear in the embryo before the neurones are differentiated. They may have other functions than neurotransmission during embryogenesis such as differentiation and neuronal growth. For example, serotonin may act as a morphogen. A number of neuropeptides are expressed during ontogenesis, but their function has been difficult to establish. Maybe some of them remain as evolutionary residues. Fast-switching neurotransmitters like the excitatory amino acids and the more ionotropic receptors dominate in the human brain, but appear probably later during evolution as well as during ontogeny. METHODS: The distribution of catecholamines during development has been analysed with a fluorescence method, while most of the other neurotransmitters have been mapped with immunohistochemical methods. The classical method to determine the physiological role of a neurotransmitter or modulator is to study the physiological effect of its antagonist, blocking the endogenous activity. By transgenic technique, the genes encoding for enzymes involved in the synthesis of neurotransmitters can be knocked-out. MAJOR FINDINGS: Pharmacological blocking of endogenous activity has, for example, demonstrated that adenosine suppresses fetal respiration. Knocking out the dopamine beta-hydroxylase gene results in fetal death, suggesting that noradrenaline is essential for survival. Some neurotransmitters change their effect during embryogenesis, e.g. GABA which is excitatory in the embryo, but inhibitory after birth due to a switch from a high to low chloride content in the nerve cells. It is possible that this is of importance for the wiring of neuronal network in early life. NMDA receptors dominate in the foetus, while kainate and AMPA receptors appear later. At birth, there is a surge of neurotransmitters such as catecholamines, which may be of importance for the neonatal adaptation. CONCLUSIONS: Neurotransmitters and modulators are not only important for the neural trafficking in the embryo, but also for the development of the neuronal circuits. Prenatal or neonatal stress (hypoxia), as well as various drugs, may disturb the wiring and cause long-term behavioural effects (fetal and neonatal programming).
Adult↗
Amino acid precursors of monoamine neurotransmitters and some factors influencing their supply to the brain.
There is evidence that changes in the concentrations of the monoamine neurotransmitters within the brain are associated with changes in mental processes, with disorders of control of movement and with certain neuropsychiatric diseases. These neurotransmitters are synthesized in the brain from aromatic amino acid precursors that have to be obtained from the circulating blood. In this study some factors which alter the rates of entry of four amino acids (the important neurotransmitter precursors L-tyrosine and L-tryptophan, as well as L-phenylalanine and L-histidine) into the brain have been studied and the findings considered in relation to conditions in which the quantities of one or more of the monoamine neurotransmitters formed within the cerebral cells may be either too large or too small. Thus too little neurotransmitter will be formed if competition between amino acids for the carriers transporting them into the cerebral cells causes the exclusion of a large proportion of any of the aromatic amino acid precursors from the brain. ,or example, L-tryptophan is partially excluded from the brain if a raised level of any one of several other amino acids is maintained in the circulation. Of these, L-phenylalanine inhibits the transport of L-tryptophan into the brain most effectively, while aromatic amino acids in general exclude L-tryptophan more effectively than do other neutral amino acids. Over-production of one or more of the monoamine neurotransmitters is likely to occur when there is too much of one of the aromatic amino acid precursors in the brain cells as a result of abnormally high uptake from the blood, or as a result of their release by an excessive breakdown of the protein within these cells. Underproduction of neurotransmitters may occur in certain disease states, such as some aminoacidurias or Parkinsonism. We have listed some conditions associated with altered mental states or motor disability in which over- or under-production of monoamine neurotransmitters may occur and have tried to relate the findings in human disease with our experimental results.
Amino Acids, Essential↗
Determination of the chemical mechanism of neurotransmitter receptor-mediated reactions by rapid chemical kinetic techniques.
Rapid chemical reaction techniques play an important role in unraveling the mechanism of reactions mediated by soluble proteins, including enzymes involved in the regulation of intracellular processes and the biosynthesis of proteins and nucleic acids. Regulatory proteins change conformation rapidly and must, therefore, be studied in the microsecond-to-millisecond time region. Similar techniques for investigating reactions mediated by membrane-bound neurotransmitter receptors were not available, and the mechanisms of the reactions are poorly understood. These proteins must be studied in a membrane-bound form in cells or vesicles, over a wide range of reactant concentrations, and in the microsecond-to-millisecond time region. Four rapid-mixing techniques for making kinetic measurements in the microsecond and millisecond time regions have now been developed for investigating neurotransmitter receptors in the membranes of neurons and muscle cells, thus extending chemical kinetic approaches to membrane-bound proteins and intercellular processes. Neurotransmitter receptors regulate transmission of signals between neurons (approximately 10(12) in the human nervous system), thereby allowing perception of stimuli, integration and storage of information, and reaction to the environment. Six structurally related neurotransmitter receptors, and many isoforms, have been identified by use of recombinant DNA technology. Modern electrophysiological techniques show that these different proteins, upon binding a specific chemical signal (neurotransmitter), transiently open transmembrane channels, which are characterized by their ion selectivity, conductance, and lifetime. To be able to account for the receptor-mediated voltage changes that trigger signal transmission between cells, we still need to know the concentration of open receptor-channels. This concentration changes with time and is affected by the concentration of neurotransmitter. Rapid reaction techniques are particularly suitable for determining the relationship between neurotransmitter concentration and the time-dependent concentration of the open receptor-channels. The four rapid reaction techniques adapted or developed for studying receptor mechanisms are quench- and stopped-flow, adapted for use with vesicles, and cell-flow and laser-pulse photolysis for use with single cells. The approach was initiated when it was found that the neurotransmitter receptors desensitize (become transiently inactive) faster, by almost two orders of magnitude, than was believed. Before fast reaction techniques were used, the chemical properties of only desensitized forms were investigated, although this was not recognized. So far, the chemical mechanism(s) of the excitatory (cation-specific) acetylcholine receptor in membrane vesicles, electroplax cells, and single clonal cells, and the inhibitory (anion-specific) gamma-aminobutyric acid (GABA) receptor in primary cerebral cortical cells have been investigated with the new techniques.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Phosphorylation of B-50 (GAP43) is correlated with neurotransmitter release in rat hippocampal slices.
Recent studies have demonstrated that phorbol diesters enhance the release of various neurotransmitters. It is generally accepted that activation of protein kinase C (PKC) is the mechanism by which phorbol diesters act on neurotransmitter release. The action of PKC in neurotransmitter release is very likely mediated by phosphorylation of substrate proteins localized in the presynaptic nerve terminal. An important presynaptic substrate of PKC is B-50. To investigate whether B-50 mediates the actions of PKC in neurotransmitter release, we have studied B-50 phosphorylation in intact rat hippocampal slices under conditions that stimulate or inhibit PKC and neurotransmitter release. The slices were labelled with [32P]orthophosphate. After treatment, the slices were homogenized, B-50 was immunoprecipitated from the slice homogenate, and the incorporation of 32P into B-50 was determined. Chemical depolarization (30 mM K+) and the presence of phorbol diesters, conditions that stimulate neurotransmitter release, separately and in combination, also enhance B-50 phosphorylation. Polymyxin B, an inhibitor of PKC and neurotransmitter release, decreases concentration dependently the depolarization-induced stimulation of B-50 phosphorylation. The effects of depolarization are not detectable at low extracellular Ca2+ concentrations. It is concluded that in rat hippocampal slices B-50 may mediate the action of PKC in neurotransmitter release.
Animals↗
Nerve-driven immunity. The direct effects of neurotransmitters on T-cell function.
We carried out studies to explore whether neurotransmitters can directly interact with their T-cell-expressed receptors, leading to either activation or suppression of various T-cell functions. Human and mouse T cells were thus exposed directly to neurotransmitters in the absence of any additional molecule, and various functions were studied, among them cytokine secretion, proliferation, and integrin-mediated adhesion and migration. In this review, I describe the effects of four neuropeptides: somatostatin (SOM), calcitonin-gene-related-peptide (CGRP), neuropeptide Y (NPY), and substance P (Sub P), and one non-peptidergic neurotransmitter--dopamine. We found that SOM, NPY, CGRP, and dopamine interact directly with T cells, leading to the activation of beta 1 integrins and to the subsequent integrin-mediated T-cell adhesion to a component of the extracellular matrix. In contrast, Sub P had a reverse effect--full blockage of integrin-mediated T-cell adhesion triggered by a variety of signals. Each of these neurotransmitters exerted its effect through direct interaction with its specific receptor on the T-cell surface, since the effect was fully blocked by the respective receptor-antagonist. Taken together, this set of findings indicates that neurotransmitters can directly interact with T cells and provide them with either positive (integrin-activating, pro-adhesive) or negative (integrin-inhibiting, anti-adhesive) signals. We further found that the above neurotransmitters, by direct interaction with their specific receptors, drove T cells (of the Th0, Th1, and Th2 phenotypes) into the secretion of both typical and atypical ("forbidden") cytokines. These results suggested that neurotransmitters can substantially affect various cytokine-dependent T-cell activities. As a whole, our studies suggest an important and yet unrecognized role for neurotransmitters in directly dictating or modulating numerous T-cell functions under physiological and pathological conditions.
Animals↗
Convergent and reciprocal modulation of a leak K+ current and I(h) by an inhalational anaesthetic and neurotransmitters in rat brainstem motoneurones.
Neurotransmitters and volatile anaesthetics have opposing effects on motoneuronal excitability which appear to reflect contrasting modulation of two types of subthreshold currents. Neurotransmitters increase motoneuronal excitability by inhibiting TWIK-related acid-sensitive K+ channels (TASK) and shifting activation of a hyperpolarization-activated cationic current (I(h)) to more depolarized potentials; on the other hand, anaesthetics decrease excitability by activating a TASK-like current and inducing a hyperpolarizing shift in I(h) activation. Here, we used whole-cell recording from motoneurones in brainstem slices to test if neurotransmitters (serotonin (5-HT) and noradrenaline (NA)) and an anaesthetic (halothane) indeed compete for modulation of the same ion channels - and we determined which prevails. When applied together under current clamp conditions, 5-HT reversed anaesthetic-induced membrane hyperpolarization and increased motoneuronal excitability. Under voltage clamp conditions, 5-HT and NA overcame most, but not all, of the halothane-induced current. When I(h) was blocked with ZD 7288, the neurotransmitters completely inhibited the K+ current activated by halothane; the halothane-sensitive neurotransmitter current reversed at the equilibrium potential for potassium (E(K)) and displayed properties expected of acid-sensitive, open-rectifier TASK channels. To characterize modulation of I(h) in relative isolation, effects of 5-HT and halothane were examined in acidified bath solutions that blocked TASK channels. Under these conditions, 5-HT and halothane each caused their characteristic shift in voltage-dependent gating of I(h). When tested concurrently, however, halothane decreased the neurotransmitter-induced depolarizing shift in I(h) activation. Thus, halothane and neurotransmitters converge on TASK and I(h) channels with opposite effects; transmitter action prevailed over anaesthetic effects on TASK channels, but not over effects on I(h). These data suggest that anaesthetic actions resulting from effects on either TASK or hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in motoneurones, and perhaps at other CNS sites, can be modulated by prevailing neurotransmitter tone.
Anesthetics, Inhalation↗
Assessment of dynamic neurotransmitter changes with bolus or infusion delivery of neuroreceptor ligands.
To describe the effect of endogenous dopamine on [11C]raclopride binding, we previously extended the conventional receptor ligand model to include dynamic changes in neurotransmitter concentration. Here, we apply the extended model in simulations of neurotransmitter competition studies using either bolus or bolus-plus-infusion (B/I) tracer delivery. The purpose of this study was (1) to develop an interpretation of the measured change in tracer binding in terms of underlying neurotransmitter changes, and (2) to determine tracer characteristics that maximize sensitivity to neurotransmitter release. A wide range of kinetic parameters was tested based on existing reversible positron emission tomography tracers. In simulations of bolus studies, the percent reduction in distribution volume (deltaV) caused by a neurotransmitter pulse was calculated. For B/I simulations, equilibrium was assumed, and the maximum percent reduction in tissue concentration (deltaC) after neurotransmitter release was calculated. Both deltaV and deltaC were strongly correlated with the integral of the neurotransmitter pulse. The values of deltaV and deltaC were highly dependent on the kinetic properties of the tracer in tissue, and deltaV could be characterized in terms of the tissue free tracer concentration. The value of deltaV was typically maximized for binding potentials of approximately 3 to 10, with deltaC being maximized at binding potentials of approximately 1 to 2. Both measures increased with faster tissue-to-blood clearance of tracer and lower nonspecific binding. These simulations provide a guideline for interpreting the results of neurotransmitter release studies and for selecting radiotracers and experimental design.
Brain↗