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    Differential regulation of GABAB receptor trafficking by different modes of N-methyl-D-aspartate (NMDA) receptor signaling

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    J. Biol. Chem.-2014-Kantamneni-6681-94.pdf (6.274Mb)
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    Publication date
    2014-01-14
    Author
    Kantamneni, Sriharsha
    Gonzàlez-Gonzàlez, I.M.
    Luo, J.
    Cimarosti, H.
    Jacobs, S.C.
    Jaafari, N.
    Henley, J.M.
    Keyword
    Chem-LTP; G Protein-coupled Receptors (GPCR); GABA Receptors; GABAB Receptor; Glutamate Receptor Ionotropic (AMPA, NMDA); Neurodegeneration; Neurotransmitter Receptors; Oxygen-glucose Deprivation (OGD); Receptor Endocytosis; Receptor Recycling
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    © 2014 American Society for Biochemistry and Molecular Biology. Reproduced in accordance with the publisher's self-archiving policy.
    Peer-Reviewed
    Yes
    
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    Abstract
    Inhibitory GABAB receptors (GABABRs) can down-regulate most excitatory synapses in the CNS by reducing postsynaptic excitability. Functional GABABRs are heterodimers of GABAB1 and GABAB2 subunits and here we show that the trafficking and surface expression of GABABRs is differentially regulated by synaptic or pathophysiological activation of NMDA receptors (NMDARs). Activation of synaptic NMDARs using a chemLTP protocol increases GABABR recycling and surface expression. In contrast, excitotoxic global activation of synaptic and extrasynaptic NMDARs by bath application of NMDA causes the loss of surface GABABRs. Intriguingly, exposing neurons to extreme metabolic stress using oxygen/glucose deprivation (OGD) increases GABAB1 but decreases GABAB2 surface expression. The increase in surface GABAB1 involves enhanced recycling and is blocked by the NMDAR antagonist AP5. The decrease in surface GABAB2 is also blocked by AP5 and by inhibiting degradation pathways. These results indicate that NMDAR activity is critical in GABABR trafficking and function and that the individual subunits can be separately controlled to regulate neuronal responsiveness and survival.
    URI
    http://hdl.handle.net/10454/8125
    Version
    Published version
    Citation
    Kantamneni S, Gonzàlez-Gonzàlez IM, Luo J et al (2014) Differential regulation of GABAB receptor trafficking by different modes of N-methyl-D-aspartate (NMDA) receptor signaling. The Journal of Biological Chemistry. 289(10): 6681-6694.
    Link to publisher’s version
    http://dx.doi.org/10.1074/jbc.M113.487348
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      Cross-talk and regulation between glutamate and GABAB receptors

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      Brain function depends on co-ordinated transmission of signals from both excitatory and inhibitory neurotransmitters acting upon target neurons. NMDA, AMPA and mGluR receptors are the major subclasses of glutamate receptors that are involved in excitatory transmission at synapses, mechanisms of activity dependent synaptic plasticity, brain development and many neurological diseases. In addition to canonical role of regulating presynaptic release and activating postsynaptic potassium channels, GABAB receptors also regulate glutamate receptors. There is increasing evidence that metabotropic GABAB receptors are now known to play an important role in modulating the excitability of circuits throughout the brain by directly influencing different types of postsynaptic glutamate receptors. Specifically, GABAB receptors affect the expression, activity and signaling of glutamate receptors under physiological and pathological conditions. Conversely, NMDA receptor activity differentially regulates GABAB receptor subunit expression, signaling and function. In this review I will describe how GABAB receptor activity influence glutamate receptor function and vice versa. Such a modulation has widespread implications for the control of neurotransmission, calcium-dependent neuronal function, pain pathways and in various psychiatric and neurodegenerative diseases.
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      Modulation of Neurotransmission by the GABAB Receptor

      Kantamneni, Sriharsha (2016-12-20)
      Most inhibitory signals are mediated via γ-aminobutyric acid (GABA) receptors whereas glutamate receptors mediate most excitatory signals (Trends Neurosci 14:515–519, 1991; Annu Rev Neurosci 17:31–108, 1994). Many factors influence the regulation of excitatory and inhibitory synaptic inputs on a given neuron. One important factor is the subtype of neurotransmitter receptor present not only at the correct location to receive the appropriate signals but also their abundance at synapses (Pharmacol Rev 51: 7–61, 1999; Cold Spring Harb Perspect Biol 3, 2011). GABAB receptors are G-protein-coupled receptors and different subunits dimerise to form a functional receptor. GABAB receptor subunits are widely expressed in the brain and by assembling different isoform combinations and accessory proteins they produce variety of physiological and pharmacological profiles in mediating both inhibitory and excitatory neurotransmission. This chapter will describe the understanding of the molecular mechanisms underlying GABAB receptor regulation of glutamate and GABAA receptors and how they modulate excitatory and inhibitory neurotransmission.
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