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GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotro...
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GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals. The gene encoding a GABA(B) receptor (GABA(B)R1) has been cloned; however, when expressed in mammalian cells this receptor is retained as an immature glycoprotein on intracellular membranes and exhibits low affinity for agonists compared with the endogenous receptor on brain membranes. Here we report the cloning of a complementary DNA encoding a new subtype of the GABAB receptor (GABA(B)R2), which we identified by mining expressed-sequence-tag databases. Yeast two-hybrid screening showed that this new GABA(B)R2-receptor subtype forms heterodimers with GABA(B)R1 through an interaction at their intracellular carboxy-terminal tails. Upon expression with GABA(B)R2 in HEK293T cells, GABA(B)R1 is terminally glycosylated and expressed at the cell surface. Co-expression of the two receptors produces a fully functional GABA(B) receptor at the cell surface; this receptor binds GABA with a high affinity equivalent to that of the endogenous brain receptor. These results indicate that, in vivo, functional brain GABA(B) receptors may be heterodimers composed of GABA(B)R1 and GABA(B)R2.
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Aims: gamma-aminobutyric acid (GABA) mediates its physiological effects through the GABA(A) and GABA(B) receptors. In this study the putative expression of GABA(A)R and GABA(B)R subunits in human myometrium tissue was investigated.
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GABA(A) receptors (GABA(A)Rs) are ligand-gated ion channels that mediate inhibitory neurotransmission in the central nervous system (CNS). They are members of the Cys-loop receptor family and display marked structural and function...
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GABA(A) receptors (GABA(A)Rs) are ligand-gated ion channels that mediate inhibitory neurotransmission in the central nervous system (CNS). They are members of the Cys-loop receptor family and display marked structural and functional heterogeneity. Many GABA(A)Rs receptor subtypes are allosterically modulated by benzodiazepines (BDZs), which are drugs extensively used as anxiolytics, sedative-hypnotics and anticonvulsants. One high-affinity site and at least three additional low-affinity sites for BDZ recognition have been identified in several heteromeric and homomeric variants of the GABA(A)Rs (e.g.: alpha 1 beta 2 gamma 2, alpha 1 beta 2/3, beta 3, etc.). However, the modulation of homomeric GABA(A)rho Rs by BDZs was not previously revealed, and these receptors, for a long a time, were assumed to be fully insensitive to the actions of these drugs. In the present study, human homomeric GABA(A)rho 1 receptors were expressed in Xenopus oocytes and GABA-evoked responses electrophysiologically recorded in the presence or absence of BDZs. GABA(A)rho 1 receptor-mediated responses were modulated by diazepam and 4'-chlorodiazepam in the micromolar range, in a concentration-dependent, voltage-independent and reversible manner. Diazepam produced potentiating effects on GABA-evoked Cl- currents and 4'-Cl diazepam induced biphasic effects depending on the GABA concentration, whereas Ro15-4513 and alprazolam were negative modulators. BDZ actions were insensitive to flumazenil. Other BDZs showed negligible activity at equivalent experimental conditions. Our results suggest that GABA(A)rho 1 receptor function can be selectively and differentially modulated by BDZs. (C) 2014 Elsevier B.V. All rights reserved.
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Moringa oleifera Lam. (MO), which is widely consumed as both food and herbal medicine in tropical and subtropical regions, has a wide spectrum of health benefits. Yet, whether the oil obtained from MO seeds could affect (improve) ...
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Moringa oleifera Lam. (MO), which is widely consumed as both food and herbal medicine in tropical and subtropical regions, has a wide spectrum of health benefits. Yet, whether the oil obtained from MO seeds could affect (improve) the sleep activity remains unclear. Herein, we used the locomotor activity, pentobarbital-induced sleeping, and pentetrazol-induced convulsions test to examine sedative-hypnotic effects (SHE) of MO oil (MOO) and explored the underlying mechanisms. Besides, the main components of MOO like oleic acid, beta-Sitosterol, and Stigmasterol were also evaluated. The results showed that they possessed good SHE. Except for oleic acid and Stigmasterol, they could significantly elevate gamma-amino butyric acid (GABA) and reduce glutamic acid (Glu) levels in the hypothalamus of mice. Moreover, SHE was blocked by picrotoxin, flumazenil, and bicuculline, except for oleic acid, which could not be antagonized by picrotoxin. Molecular mechanisms showed that MOO and beta-Sitosterol significantly upregulated the amount of protein-level expression of Glu decarboxylase-65 (GAD(65)) and alpha(1)-subunit of GABA(A) receptors in the hypothalamus of mice, not affecting GAD(67), gamma(2) subunits. These data indicated that MOO modulates sleep architectures via activation of the GABA(A)-ergic systems.
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Much evidence implicates the serotonergic regulation of the amygdala in anxiety. Thus the present study was undertaken to characterize the influence of serotonin (5-HT) on principal neurons (PNs) of the rat lateral amygdala (LA). ...
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Much evidence implicates the serotonergic regulation of the amygdala in anxiety. Thus the present study was undertaken to characterize the influence of serotonin (5-HT) on principal neurons (PNs) of the rat lateral amygdala (LA). using whole cell recordings in vitro. Because inhibition is a major determinant of PN activity, we focused on the control of GABAergic transmission by 5-HT. IPSCs were elicited by local electrical stimulation of LA in the presence of glutamate receptor antagonists. We found that 5-HT reduces GABA(A) inhibitory postsynaptic currents (IPSCs) via presynaptic 5-HT1B, receptors. While the presynaptic inhibition of GABA release also attenuated GABA(B) currents, this effect was less pronounced than for GABA(A) currents because 5-HT also induced a competing postsynaptic enhancement of GABA(B) currents. That is, GABA(B) currents elicited by pressure application of GABA or baclofen were enhanced by 5-HT. In addition, we obtained evidence suggesting that 5-HT differentially regulates distinct subsets of GABAergic synapses. Indeed, GABA(A) IPSCs were comprised of two components: a relatively 5-HT-insensitive IPSC that had a fast time course and a 5-HT-insensitive component that had a slower time course. Because the relative contribution of these two components varied depending on whether neurons were recorded at proximity versus at a distance from the stimulating electrodes, we speculate that distinct subtypes of local-circuit cells contribute the two contingents of GABAergic synapses. Overall, our results indicate that 5-HT is a potent regulator of synaptic inhibition in LA.
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Although an extensive body of literature confirmed gamma-aminobutyric acid (GABA) as mediator within the enteric nervous system (ENS) controlling gastrointestinal (GI) function, the true significance of GABAergic signalling in the...
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Although an extensive body of literature confirmed gamma-aminobutyric acid (GABA) as mediator within the enteric nervous system (ENS) controlling gastrointestinal (GI) function, the true significance of GABAergic signalling in the gut is still a matter of debate. GABAergic cells in the bowel include neuronal and endocrine-like cells, suggesting GABA as modulator of both motor and secretory GI activity. GABA effects in the GI tract depend on the activation of ionotropic GABA(A) and GABA(C) receptors and metabotropic GABA(B) receptors, resulting in a potential noteworthy regulation of both the excitatory and inhibitory signalling in the ENS. However, the preservation of GABAergic signalling in the gut could not be limited to the maintenance of physiologic intestinal activity. Indeed, a series of interesting studies have suggested a potential key role of GABA in the promising field of neuroimmune interaction, being involved in the modulation of immune cell activity associated with different systemic and enteric inflammatory conditions. Given the urgency of novel therapeutic strategies against chronic immunity-related pathologies, i.e. multiple sclerosis and Inflammatory Bowel Disease, an in-depth comprehension of the enteric GABAergic system in health and disease could provide the basis for new clinical application of nerve-driven immunity. Hence, in the attempt to drive novel researches addressing both the physiological and pathological importance of the GABAergic signalling in the gut, we summarized current evidence on GABA and GABA receptor function in the different parts of the GI tract, with particular focus on the potential involvement in the modulation of Cl motility and inflammation. (C) 2014 Elsevier Ltd. All rights reserved.
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The central nervous system, once thought to be a site of immunological privilege, has since been found to harbour immunocompetent cells and to communicate with the peripheral nervous system. In the central nervous system (CNS), gl...
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The central nervous system, once thought to be a site of immunological privilege, has since been found to harbour immunocompetent cells and to communicate with the peripheral nervous system. In the central nervous system (CNS), glial cells display immunological responses to pathological and physiological stimuli through pro-and anti-inflammatory cytokine and chemokine signalling, antigen presentation and the clearing of cellular debris through phagocytosis. While this neuroinflammatory signalling can act to reduce neuronal damage and comprises a key facet of CNS homeostasis, persistent inflammation or auto-antigen-mediated immunoreactivity can induce a positive feedback cycle of neuroinflammation that ultimately results in necrosis of glia and neurons. Persistent neuroinflammation has been recognised as a major pathological component of virtually all neurodegenerative diseases and has also been a focus of research into the pathology underlying psychiatric disorders. Thus, pharmacological strategies to curb the pathological effects of persistent neuroinflammation are of interest for many disorders of the CNS. Accumulating evidence suggests that GABAergic activities are closely bound to immune processes and signals, and thus the GABAergic neurotransmitter system might represent an important therapeutic target in modulating neuroinflammation. Here, we review evidence that inflammation induces changes in the GABA neurotransmitter system in the CNS and that GABAergic signalling exerts a reciprocal influence over neuroinflammatory processes. Together, the data support the hypothesis that the GABA system is a potential therapeutic target in the modulation of central inflammation. (C) 2016 Elsevier Inc. All rights reserved.
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GABA(A) receptors are important for inhibition in the CNS where neurosteroids and protein kinases are potent endogenous modulators. Acting individually, these can either enhance or depress receptor function, dependent upon the typ...
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GABA(A) receptors are important for inhibition in the CNS where neurosteroids and protein kinases are potent endogenous modulators. Acting individually, these can either enhance or depress receptor function, dependent upon the type of neurosteroid or kinase and the receptor subunit combination. However, in vivo, these modulators probably act in concert to fine-tune GABA(A) receptor activity and thus inhibition, although how this is achieved remains unclear. Therefore, we investigated the relationship between these modulators at synaptic-type alpha 1 beta 3 gamma 2L and extrasynaptic-type alpha 4 beta 3 delta GABA(A) receptors using electrophysiology.
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The aim of this study was to investigate the action of general anesthetics in phospholipase C-related catalytically inactive protein (PRIP)-knockout (KO) mice that alter GABA(A) receptor signaling.
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B-type receptors for the neurotransmitter GABA (gamma-aminobutyric acid) inhibit neuronal activity through G-protein-coupled second-messenger systems, which regulate the release of neurotransmitters and the activity of ion channel...
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B-type receptors for the neurotransmitter GABA (gamma-aminobutyric acid) inhibit neuronal activity through G-protein-coupled second-messenger systems, which regulate the release of neurotransmitters and the activity of ion channels and adenylyl cyclase. Physiological and biochemical studies show that there are differences in drug efficiencies at different GABA(B) receptors, so it is expected that GABA(B)-receptor (GABA(B)R) subtypes exist. Two GABA(B)-receptor splice variants have been cloned (GABA(B)R1a and GABA(B)R1b), but native GABA(B) receptors and recombinant receptors showed unexplained differences in agonist-binding potencies. Moreover, the activation of presumed effector ion channels in heterologous cells expressing the recombinant receptors proved difficult. Here we describe a new GABA(B) receptor subtype, GABA(B)R2, which does not bind available GABA(B) antagonists with measurable potency. GABA(B)R1a, GABA(B)R1b and GABA(B)R2 alone do not activate Kir3-type potassium channels efficiently, but co-expression of these receptors yields a robust coupling to activation of Kir3 channels. We provide evidence for the assembly of heteromeric GABA(B) receptors in vivo and show that GABA(B)R2 and GABA(B)R1a/b proteins immunoprecipitate and localize together at dendritic spines. The heteromeric receptor complexes exhibit a significant increase in agonist- and partial-agonist-binding potencies as compared with individual receptors and probably represent the predominant native GABA(B) receptor. Heteromeric assembly among G-protein-coupled receptors has not, to our knowledge, been described before.
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