2 edition of Physiological and pathological implications underlying GABAA receptor trafficking. found in the catalog.
Physiological and pathological implications underlying GABAA receptor trafficking.
William Young-Ho Ju
Written in English
gamma-aminobutyric acid type A receptors (GABAARs) are ligand gated ion channels that mediate the majority of rapid synaptic inhibition in the brain. These receptors are hetero-pentameric ion channels, and are typically composed of alpha, beta, and gamma subunits. Although the regulation of GABAAR channel activity is likely controlled by a number of different factors, one essential factor that underlies the efficacy of this type of synaptic inhibition is the regulation of GABA AR cell surface expression and stability. We developed new methods to examine the delivery and insertion of receptors into the synaptic and plasma membrane of living cells: both an antibody-based blocking and insertion assay and an enzyme cleavable epitope system were developed to study both basal and regulated GABAA receptor trafficking. In addition, as previous reports have implicated the beta2 subunit as an important contributor to GABAA receptor trafficking, while the gamma2 subunit is not, we generated various beta2gamma2 chimeric proteins and expressed these along with the alpha1 subunit in heterologous HEK 293 cells and examined their cell surface expression and functionality. Using these and other methods we demonstrate that the major intracellular loop of the beta2 subunit is required for cell surface expression but is insufficient to produce a functional alpha 1-beta2 receptor. Further work showed that the beta 2 N-terminal domain is required for full receptor function but not for cell surface expression. We next examined the regulation of GABAA receptor trafficking with a directly interacting GPCR, the D5 dopamine receptor. We showed that these receptors co-traffic and that this co-trafficking is dependent upon the competition for interaction with a GABAA receptor associated protein (GABARAP). Lastly we have found that GABAA receptors undergo endocytosis and that the endocytosis acts as a trigger for apoptosis but this is both specific and developmentally regulated. Taken as a whole our results show different forms of regulation of GABAA receptor trafficking under physiological conditions, the regulation of trafficking and how alterations in trafficking may play a role in pathology.
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Modulation of GABAA receptor activity by phosphorylation and receptor trafficking: implications for the efficacy of synaptic inhibition. Curr Opin Neurobiol –, Crossref PubMed ISI Google Scholar; 79 Kjems LL, Kirby BM, Welsh EM, Veldhuis JD, Straume M, McIntyre SS, Yang D, Lefebvre P, Butler by: The traditional emphasis on developing high specificity pharmaceuticals ("magic bullets") for the treatment of Neurological and Psychiatric disorders is being challenged by emerging pathophysiology concepts that view disease states as abnormal interactions within complex networks of molecular and cellular components. So-called network pharmacology Cited by: The capability of the brain to change functionally in response to sensory experience is most active during early stages of development but it decreases later in life when major alterations of neuronal network structures no longer take place in response to experience. This view has been recently challenged by experimental strategies based on the enhancement of environmental Cited by: A dynamic balance between the excitatory and inhibitory neurotransmitters glutamate and GABA is critical for maintaining proper neuronal activity in the brain. This balance is partly achieved via presynaptic interactions between glutamatergic and GABAAergic synapses converging into the same targets. Here, we show that in hypothalamic magnocellular Cited by:
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Γ-Aminobutyric acid type A (GABA A) receptors mediate the majority of fast synaptic inhibition in the mammalian brain, controlling activity both at the network and cellular diverse functions of GABA in the central nervous system are matched not just by the heterogeneity of GABA A receptors, but also the complex trafficking mechanisms and protein-protein Cited by: These changes include GABAA receptor subunit expression, intracellular trafficking and phosphorylation.
These adaptations are relevant to different physiological, pathological and pharmacological conditions and, in most cases, are associated with the development of by: 4.
Regulated endocytosis of neurotransmitter receptors is known to underlie physiological and pathological adaptations of neural excitability. Endocytosis of GABA A Rs occurs primarily via clathrin- and dynamin-dependent mechanisms that are facilitated by interactions of the GABA A R β and γ subunits with the clathrin adaptor protein AP2 (Kittler et al.,Kittler et al.,Cited by: GABAA receptors mediate most inhibitory synaptic transmission, and their assembly and trafficking in neurons is tightly regulated.
Moss and colleagues review our current knowledge about the Cited by: Gamma-aminobutyric acid type A receptors (GABAARs) are the principal mediators of inhibitory transmission in the mammalian central nervous system.
GABAARs can be localized at post-synaptic inhibitory specializations or at extrasynaptic sites. While synaptic GABAARs are activated transiently following the release of GABA from presynaptic vesicles, Cited by: These physiological, and often pathological, destabilizing events can take the form of physical growth of the nerve cell during development, developmental or disease‐related changes in ion channels, receptors, transporters, or essentially anything that can significantly modify the excitability of the by: A Receptor Trafficking during Status Epilepticus December 4, Howard P.
Goodkin, MD, PhD receptors is a potential mechanism to partially explain pharmacoresistance. Treatment implications •Treat SE early •Therapies that target the endocytic machinery Pellock et al.
Epilepsy Behav, Treatment implicationsFile Size: KB. Clustering of GABAA receptors at inhibitory synapses is important for maintaining the correct balance of excitation and inhibition in the brain.
Smith et al. reveal a signaling mechanism at inhibitory synapses involving the scaffold GIT1, which anchors βPIX to the inhibitory synaptic site and activates Rac1 and PAK, thereby stabilizing by: Pharmacology of the GABAA Receptor.
Chapter In book: Handbook of Contemporary Neuropharmacology physiological and pathological conditions that involve intense recept or.
Since the pioneering discovery of the rapid CNS depressant actions of steroids by the “father of stress,” Hans Seyle 70 years ago, brain-derived “neurosteroids” have emerged as powerful endogenous modulators of neuronal excitability.
The majority of the intervening research has focused on a class of naturally occurring steroids that are metabolites of progesterone and Cited by: protein interactions that generate and maintain an appropriate receptor cell-surface localization.
In this Review, we discuss recent progress in our understanding of the dynamic regulation of GABA A R composition, trafficking to and from the neuronal surface, and lateral movement of receptors between synaptic and extrasynaptic Size: 1MB. Not only are GABAA receptors activated transiently by GABA released at synapses, but high affinity, extrasynaptic GABAAreceptors are also activated by ambient, extracellular GABA as a more Cited by: The γ-aminobutyric acid (GABA) type A receptor system, the main fast-acting inhibitory neurotransmitter system in the brain, is the pharmacological target for many drugs used clinically to treat, for example, anxiety disorders and epilepsy, and to induce and maintain sedation, sleep, and anesthesia.
These drugs facilitate the function of pentameric GABAA receptors Cited by: GABAA Receptor. GABAA receptors are the primary mediators of fast inhibitory synaptic transmission in the central nervous system, and are formed by pentameric assemblies of multiple subunit subtypes (α1–α6, β1–β3, γ1–γ3, δ, ϵ, π, θ, and ρ1–ρ3) that form chloride ion channels.
From: Encyclopedia of Basic Epilepsy Research, Mechanisms of GABA A receptor assembly and trafficking: implications for the modulation of inhibitory neurotransmission. Mol Neurobiol –, Crossref PubMed ISI Google Scholar; Kittler JT, Moss SJ. Modulation of GABA A receptor activity by phosphorylation and receptor trafficking: implications for the efficacy of synaptic Cited by: Abstract: The trafficking of ionotropic glutamate (AMPA, NMDA and kainate) and GABAA receptors in and out of, or laterally along, the postsynaptic membrane has recently emerged as an important mechanism in the regulation of synaptic function, both under physiological and pathological conditions, such as information processing, learning and memory formation, Cited by: This process is negatively regulated by Plic-1, which binds directly to receptor α- and β-subunits, prolonging their ER residence times.
Within the Golgi, receptors bind to complexes of GABARAP/NSF, facilitating their transport to the plasma membrane. BIG2 is also found within the Golgi and modulates receptor forward trafficking.
Synergistic Roles of GABA(A) Receptors and SK Channels in Regulating Thalamocortical Oscillations Article in Journal of Neurophysiology (1) May with 39 Reads How we measure 'reads'.
Because GABARAPL2 appears to have a physiological role in mediating GABA A receptor trafficking and this function may be compromised in autophagy-deficient neurons, we attempted to replenish the Cited by: 7.
The physical association between GABA A and GABA B receptors that we have observed may play an analogous role in underlying physiological cross-talk between the two receptor types. Along these lines, we found that co-expression with GABA B R1 modestly increased the potency of GABA acting at GABA A receptors expressed in oocytes.
Gephyrin is a central element that anchors, clusters and stabilizes glycine and γ-aminobutyric acid type A receptors at inhibitory synapses of the mammalian brain. It self-assembles into a Cited by: Abstract: GABA A receptors containing the α 5 subunit (α 5 GABA A Rs) are found mainly in the hippocampus where they mediate a tonic chloride leak current and contribute a slow component to GABAergic inhibitory synaptic currents.
Their inhibitory effect on the excitability of hippocampal neurons at least partly explains why changes in the level of activity of α 5 GABA A Rs affect Cited by: It summarizes how receptor modifications influence trafficking, discusses mechanisms that regulate GPCR trafficking to and from the plasma membrane, reviews the relationship between trafficking and signaling, and considers the implications of GPCR trafficking to.
The endocytosis of GABAA receptors was investigated in HEK cells expressing receptor α1β2- and α1β2γ2-subunit combinations. For assessment of internalized receptors by radioimmunoassay or immunofluorescence, a triple c-myc epitope was introduced into the amino terminus of the β2 subunit.
An assay based on biotin inaccessibility was used for α1 by: Ulk2 controls cortical excitatory–inhibitory balance via autophagic regulation of p62 and GABA A receptor trafficking in occur in a cell type-preferential manner through combination of both intrinsic cellular vulnerability and circuit-wide physiological demands, thereby underlying sporadic psychiatric conditions.
further implications Cited by: 7. Neuron Review GABA A Receptor Trafﬁcking-Mediated Plasticity of Inhibitory Synapses Bernhard Luscher, 1,2 3* Thomas Fuchs, and Casey L.
Kilpatrick2,3 1Department of Biology, Pennsylvania State University, University Park, PAUSA 2Department of Biochemistry & Molecular Biology, Pennsylvania State University, University Park, PAUSA 3Center for. Figure 1. (A) Chloride concentration regulatory mechanisms underlying GABAa receptor-mediated responses in immature and mature CNS neurons.
(Left): Upregulated NKCC1 is the main regulator which mediates Cl − uptake in immature CNS neurons in parallel with downregulated KCC2 or in its absence. (Right): KCC2 is the principal K-Cl cotransporter in Author: Ru Liu, Junling Wang, Shuli Liang, Guojun Zhang, Xiaofeng Yang.
Purpose: The human hypothalamic hamartoma (HH) is a rare, intrinsically epileptogenic lesion associated with gelastic seizures, but the underlying mechanisms remain unclear. Here, we examined the role of GABA A receptors in surgically resected HH tissue.
Methods: HH tissue slices ( μm) were studied using cellular electrophysiological, calcium imaging, and Cited by: Over the past two decades, research has identified extrasynaptic GABAA receptor populations that enable neurons to sense the low ambient GABA concentrations present in the extracellular space in order to generate a form of tonic inhibition not previously considered in studies of neuronal excitability.
The importance of this tonic inhibition in regulating states of Cited by: Receptors: Models for Binding, Trafficking, and Signaling bridges the gap between chemical engineering and cell biology by lucidly and practically demonstrating how a mathematical modeling approach combined with quantitative experiments can provide enhanced understanding of cell phenomena involving receptor/ligand interactions.
In stressing the need for a 5/5(1). The GABA A receptors are made up of subunits which form a receptor complex. Humans have 19 receptor subunits and are classified into α (1–6), β (1–3), γ (1–3), δ, ε, π, θ, and ρ (1−3).
The function of the receptor is different according to how the pentameric complex is put together. The most common complex that includes around 40% of the GABA A receptors is the α1β2γ2.
Modulation of GABAA receptor activity by phosphorylation and receptor trafﬁ cking: implications for the efﬁ cacy of synaptic inhibition. Modulation of GABAA receptor phosphorylation and membrane trafﬁ cking by phospholipase C-related inactive protein/protein phosphatase 1 and 2A signaling complex underlying BDNF-dependent Author: Jean-Marc Fritschy.
GABA A receptor–gephyrin interactions In striking contrast to AMPA and NMDA receptors, whose interaction with PSD‐95 has been extensively analysed in the context of synaptic plasticity and homeostasis, the interaction between GABA A R and gephyrin remains largely elusive.
Direct binding has long been considered unlikely, in the absence of Cited by: Rhythmic oscillations throughout the cortex are observed during physiological and pathological states of the brain. The thalamus generates sleep spindle oscillations and spike-wave discharges characteristic of absence epilepsy.
Much has been learned regarding the mechanisms underlying these oscillations from in vitro brain slice preparations. Valium without dependence. Individual GABAA receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects Tianze Cheng,1 Dominique Marie Wallace,2 Benjamin Ponteri,1 Mahir Tuli3 1Pitzer College, Claremont, CA, USA; 2Portland State University, Portland, OR, USA; 3University of British Columbia, Vancouver, BC, Canada Cited by: 5.
Hippocampal culture. Hippocampal neuronal cultures were prepared from hippocampal tissue isolated from 2-day-old Sprague-Dawley rats.
Neurons were isolated, plated at a density of 2 × 10 5 /cm 2 onto a confluent astroglial support layer, and maintained in a culture incubator for ≤3 wk at 37°C as has been described previously (Coulter et al.
; Sombati and DeLorenzo ; Cited by: Depending on their subunit composition, GABA A receptors can be highly sensitive to Zn 2+.Although a pathological role for Zn 2+-mediated inhibition of GABA A receptors has been postulated, no direct evidence exists that endogenous Zn 2+ can modulate GABAergic signaling in the brain.
A possible explanation is that Zn 2+ is mainly localized to a subset of Cited by: The most abundant subunit combinations in the adult brain, α1β2γ2 and α2β3γ2, constitute, respectively, ∼60% and ∼20% of all GABA receptors, the remainder probably contain α3, α4, α5, or α6 (only found in cerebellum) subunits or a δ in place of γ The α1-GABA-A receptor channels produce currents with a duration that is 6–7 Cited by: GABAergic neurons, as well as GABAA and GABAB receptors, are present in spinal cord and brain areas associated with the mediation and perception of pain (Fig.
With regard to higher brain regions, there is evidence that activation of GABAA receptors in the parafasiculus thalami induces an antinociceptive response (Reyes-Vazquez et al., ). Tonic inhibition mediated by extrasynaptic GABA A receptors (GABA A Rs) is an important regulator of neuronal excitability.
Phosphorylation by protein kinase C (PKC) provides a key mode of regulation for synaptic GABA A Rs underlying phasic inhibition; however, less attention has been focused on the plasticity of tonic inhibition and whether this can also be modulated by receptor Cited by:.
The hypothalamic-pituitary-adrenal (HPA) axis, which mediates the body's response to stress, is largely under GABAergic control.
Here we demonstrate that corticotropin-releasing hormone (CRH) neurons are modulated by the stress-derived neurosteroid, tetrahydrodeoxycorticosterone (THDOC), acting on δ subunit-containing GABAA receptors Cited by: Brain-derived neurotrophic factor, also known as BDNF, is a protein that, in humans, is encoded by the BDNF gene.
BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor. Neurotrophic factors are found in the brain and the periphery.
BDNF was first isolated from pig brain in by Yves-Alain Barde and Hans Aliases: BDNF, brain-derived neurotrophic factor. A) cause conformational changes in the GABAA receptor that lead to the closing of the Cl- ion channel.
B) stimulate the orthosteric binding site for GABA. C) precent GABA from binding to its orthosteric site. D) cause conformational changes in the GABAA receptor that lead to the opening of the Cl- ion channel.