Genetic variants of Neuregulin 1 (NRG1) and its neuronal tyrosine kinase receptor ErbB4 are associated with risk for schizophrenia, a neurodevelopmental disorder characterized by ...excitatory/inhibitory imbalance and dopamine (DA) dysfunction. To date, most ErbB4 studies have focused on GABAergic interneurons in the hippocampus and neocortex, particularly fast-spiking parvalbumin-positive (PV+) basket cells. However, NRG has also been shown to modulate DA levels, suggesting a role for ErbB4 signaling in dopaminergic neuron function. Here we report that ErbB4 in midbrain DAergic axonal projections regulates extracellular DA levels and relevant behaviors. Mice lacking ErbB4 in tyrosine hydroxylase-positive (TH+) neurons, but not in PV+ GABAergic interneurons, exhibit different regional imbalances of basal DA levels and fail to increase DA in response to local NRG1 infusion into the dorsal hippocampus, medial prefrontal cortex and dorsal striatum measured by reverse microdialysis. Using Lund Human Mesencephalic (LUHMES) cells, we show that NRG/ErbB signaling increases extracellular DA levels, at least in part, by reducing DA transporter (DAT)-dependent uptake. Interestingly, TH-Cre;ErbB4
mice manifest deficits in learning, spatial and working memory-related behaviors, but not in numerous other behaviors altered in PV-Cre;ErbB4
mice. Importantly, microinjection of a Cre-inducible ErbB4 virus (AAV-ErbB4.DIO) into the mesencephalon of TH-Cre;ErbB4
mice, which selectively restores ErbB4 expression in DAergic neurons, rescues DA dysfunction and ameliorates behavioral deficits. Our results indicate that direct NRG/ErbB4 signaling in DAergic axonal projections modulates DA homeostasis, and that NRG/ErbB4 signaling in both GABAergic interneurons and DA neurons contribute to the modulation of behaviors relevant to psychiatric disorders.
The deadliest forms of skin cancer, melanomas have a large fatality rate. In the United States of America, 196,060 new cases of melanoma are anticipated in 2020. In the past, many automated methods ...for diagnosing skin lesions have been proposed, but they have not yet proven to be very accurate. Based on skin cells’ exposure to sunlight, aberrant skin cell development frequently results in skin cancer. Ultraviolet radiation, viruses, bacteria, chemicals, and fungi are the main contributors to skin conditions. The creation of a precise computer-aided system for diagnosing breast cancer is of tremendous clinical importance. An improved machine learning framework has been developed in this research to detect skin lesions or skin cancer. Hence it is important to segment and classify the skin lesion. The research utilizes the fruit fly optimization algorithm and machine learning framework to segment and classifies skin disease and cancer. This platform's central idea is to use the fruit fly optimization algorithm (FOA) to improve two crucial SVM variables and create an FOA-based SVM (FOA-SVM) for the diagnosis of skin cancer. The integrative approach not only improves accuracy but also provides important data for more accurate classification.
The trace amine para -tyramine is structurally and functionally related to the amphetamines and the biogenic amine neurotransmitters. It is currently
thought that the biological activities elicited ...by trace amines such as p -tyramine and the psychostimulant amphetamines are manifestations of their ability to inhibit the clearance of extracellular
transmitter and/or stimulate the efflux of transmitter from intracellular stores. Here we report the discovery and pharmacological
characterization of a rat G protein-coupled receptor that stimulates the production of cAMP when exposed to the trace amines
p -tyramine, β-phenethylamine, tryptamine, and octopamine. An extensive pharmacological survey revealed that psychostimulant
and hallucinogenic amphetamines, numerous ergoline derivatives, adrenergic ligands, and 3-methylated metabolites of the catecholamine
neurotransmitters are also good agonists at the rat trace amine receptor 1 (rTAR1). These results suggest that the trace amines
and catecholamine metabolites may serve as the endogenous ligands of a novel intercellular signaling system found widely throughout
the vertebrate brain and periphery. Furthermore, the discovery that amphetamines, including 3,4-methylenedioxymethamphetamine
(MDMA; âecstasyâ), are potent rTAR1 agonists suggests that the effects of these widely used drugs may be mediated in part
by this receptor as well as their previously characterized targets, the neurotransmitter transporter proteins.
Although a glutamate-gated chloride conductance with the properties of a sodium-dependent glutamate transporter has been described in vertebrate retinal photoreceptors and bipolar cells, the ...molecular species underlying this conductance has not yet been identified. We now report the cloning and functional characterization of a human excitatory amino acid transporter, EAAT5, expressed primarily in retina. Although EAAT5 shares the structural homologies of the EAAT gene family, one novel feature of the EAAT5 sequence is a carboxy-terminal motif identified previously in N-methyl-D-aspartate receptors and potassium channels and shown to confer interactions with a family of synaptic proteins that promote ion channel clustering. Functional properties of EAAT5 were examined in the Xenopus oocyte expression system by measuring radiolabeled glutamate flux and two-electrode voltage clamp recording. EAAT5-mediated L-glutamate uptake is sodium- and voltage-dependent and chloride-independent. Transporter currents elicited by glutamate are also sodium- and voltage-dependent, but ion substitution experiments suggest that this current is largely carried by chloride ions. These properties of EAAT5 are similar to the glutamate-elicited chloride conductances previously described in retinal neurons, suggesting that the EAAT5-associated chloride conductance may participate in visual processing.
Background: Reboxetine is a potent antidepressant, with efficacy comparable to that of imipramine, desipramine, and fluoxetine, and has improved side-effect profile. The basis of its efficacy and ...improved tolerability is sought through studies of reboxetine in a number of pharmacological models of depression.
Methods: Pharmacological selectivity for uptake systems was defined by uptake and binding assays for the three monoamine uptake sites. Specificity was determined in 39 different receptor and 6 enzyme assays. In vivo selectivity was defined by measurement of neuronal firing rates in the locus coeruleus, dorsal raphe, and substantia nigra. Reserpine-induced blepharospasm and hypothermia, clonidine-induced hypothermia, defined reboxetine’s in vivo pharmacology. Reboxetine’s antidepressant potential was evaluated behaviorally by the tail-suspension test, forced swimming, and the DRL
72 operant responding test.
Results: Reboxetine is a potent, selective, and specific norepinephrine reuptake inhibitor (selective NRI) as determined by both in vitro and in vivo measurements. Unlike desipramine or imipramine, reboxetine has weak affinity (Ki > 1000 nmol/L) for muscarinic, histaminergic H1, adrenergic α
1, and dopaminergic D
2 receptors. In vivo action of reboxetine is entirely consistent with the pharmacological action of an antidepressant with preferential action at the norepinephrine reuptake site. Reboxetine showed an antidepressant profile in all tests of antidepressant activity used. Significant decreases in immobility were observed in the tail suspension test and behavioral despair test. Increased efficiency in responding was observed in the DRL
72 test.
Conclusions: Reboxetine is a potent, selective, and specific noradrenergic reuptake inhibitor. It has a superior pharmacological selectivity to existing tricyclic antidepressants and selective serotonin reuptake inhibitors when tested in a large number of in vitro and in vivo systems. Given the pharmacological profile, reboxetine is expected to be a selective and potent tool for psychopharmacological research. The use of reboxetine in the clinic will also help clarify the role norepinephrine plays in depression.
As the most predominant excitatory neurotransmitter, glutamate has the potential to influence the function of most neuronal circuits in the central nervous system. To limit receptor activation during ...signaling and prevent the overstimulation of glutamate receptors that can trigger excitotoxic mechanisms and cell death, extracellular concentrations of excitatory amino acids are tightly controlled by transport systems on both neurons and glial cells. L-Glutamate is a potent neurotoxin, and the inadequate clearance of excitatory amino acids may contribute to the neurodegeneration seen in a variety of conditions, including epilepsy, ischemia, and amyotrophic lateral sclerosis. To establish the contributions of carrier systems to the etiology of neurological disorders, and to consider their potential utility as therapeutic targets, a detailed understanding of transporter function and pharmacology is required. This review summarizes current knowledge of the structural and functional diversity of excitatory amino acid transporters and explores how they might serve as targets for drug design.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Excitatory amino acid transporters (EAATs) are the primary regulators of extracellular glutamate concentrations in the central nervous system. Among the five known human EAAT subtypes, the glial ...carriers, EAAT1 and EAAT2 have the greatest impact on clearance of glutamate released during neurotransmission. Studies of carriers expressed on neurons, Purkinje cells and photoreceptor cells (EAAT3, EAAT4 and EAAT5, respectively) suggest more subtle roles for these subtypes in regulating excitability and signalling. The data suggest that EAA transporters may influence glutamatergic transmission by regulating the amount of glutamate available to activate pre- and post-synaptic metabotropic receptors and by altering neuronal excitability through a transporter-associated anion conductance that is activated by carrier substrates. Recent studies on structural, mechanistic and physiological aspects of carrier function in a variety of model systems and organisms have led to surprising insights into how excitatory amino acid transporters shape cellular communication in the nervous system.
Uptake by Na(+)/Cl(-)-dependent neurotransmitter transporters is the principal mechanism by which extracellular biogenic amine concentrations are regulated. In addition to uptake, the cloned ...transporter proteins also elicit ion channel-like currents, but the physiological consequences of these currents are unknown. Here, whole-cell patch clamp and perforated-patch recordings show that substrates of the dopamine transporter (DAT), such as dopamine (DA) and amphetamine, increase the firing activity of rat DA neurons in culture. We found that these substrates elicit inward currents that are Na(+)-dependent and blocked by cocaine. These currents are primarily comprised of anions and result in an excitatory response in DA neurons at lower DA concentrations than are required for D2 autoreceptor activation. Thus, in addition to clearing extracellular DA, our results suggest that the currents associated with DAT modulate excitability and may regulate release of neurotransmitter from midbrain DA neurons.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The dopamine transporter plays an essential role in the modulation of dopaminergic neurotransmission by mediating the reuptake of dopamine into presynaptic neurons. In cells expressing the dopamine ...transporter, activation of protein kinase C by phorbol esters results in a significant reduction in dopamine uptake. This phorbol ester-mediated inhibition of dopamine transport is associated with a decrease in V(max), although the apparent affinity of the transporter for dopamine remains unchanged. Using a green fluorescent protein-tagged dopamine transporter stably expressed in Madin-Darby canine kidney cells, we show in live cells that the decrease in transporter activity is caused by the rapid internalization of carriers from the plasma membrane. This redistribution of the transporter is specific to phorbol ester activation and is unaffected by the presence of either substrates or inhibitors of the carrier. Upon the addition of phorbol esters, transporters at the cell surface are rapidly endocytosed through a clathrin-mediated and dynamin-dependent mechanism into early endosomes, where they colocalize with transferrin. The internalized carrier is targeted to the endosomal/lysosomal pathway and is completely degraded within 2 h of protein kinase C activation. Phorbol ester-mediated alterations in the trafficking of the dopamine transporter may serve as a mechanism for controlling extracellular dopamine levels in the central nervous system.
Excitatory amino-acid transporters (EAATs) in the central nervous system maintain extracellular glutamate concentrations below excitotoxic levels and may limit the activation of glutamate receptors. ...Here we report the cloning of a novel human aspartate/glutamate transporter, EAAT4, which is expressed predominantly in the cerebellum. The transport activity encoded by EAAT4 has high apparent affinity for L-aspartate and L-glutamate, and has a pharmacological profile consistent with previously described cerebellar transport activities. In Xenopus oocytes expressing EAAT4, L-aspartate and L-glutamate elicited a current predominantly carried by chloride ions. This chloride conductance was not blocked by components that block endogenous oocyte chloride channels. Thus EAAT4 combines the re-uptake of neurotransmitter with a mechanism for increasing chloride permeability, both of which could regulate excitatory neurotransmission.
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