Neuronal and Glial Glycine Transporters Have Different Stoichiometries

Roux, Michel J.; Supplisson, Stéphane

doi:10.1016/s0896-6273(00)80901-0

Cited by 249 publications

(318 citation statements)

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“…Because HCY's desensitization effects are occluded at high [GLY] and are blocked by the GLY site antagonist DCKA, NMDAR susceptibility to HCY in real neural circuits relies on whether the NMDAR GLY site is saturated at synapses in the brain. Data-based modeling experiments have presumed that the synaptic [GLY] in GlyT expressing brain areas is below 150 nM (Attwell et al 1993;Roux and Supplisson 2000), which, by design, resembles the concentration used in our culture experiments. D-Serine, a second in vivo coagonist of the NMDAR GLY site, is strongly expressed in the forebrain (Schell et al 1997;Wolosker 2006 for review) and may be the primary NMDAR coagonist at some synapses (Papouin et al 2012).…”

Section: Hcy Effect On Nmdar Currents Depends On Glun2 Subunit Compmentioning

confidence: 99%

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

Bolton

Phillips

Constantine‐Paton

2013

Journal of Neurophysiology

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Bolton AD, Phillips MA, Constantine-Paton M. Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition. J Neurophysiol 110: 1567-1582, 2013. First published July 17, 2013 doi:10.1152/jn.00809.2012.-N-methyl-D-aspartate receptors (NMDARs) have been linked to schizophrenia because agents that bind the receptor, like ketamine and phencyclidine, are capable of inducing schizophrenia-like symptoms. Here we show that the amino acid homocysteine (HCY), which is increased in the blood of schizophrenia patients, reduces desensitization of NMDARs in cultured mouse neurons, human embryonic kidney cells transfected with GluN1 ϩ GluN2A, GluN2B, or GluN2D subunits, and hippocampal slices. HCY also alters the peak amplitude of NMDAR currents, depending on the GluN2 subunit the receptor contains; GluN1 ϩ GluN2A-containing NMDARs show an increase in peak amplitude when exposed to HCY, while GluN1 ϩ GluN2B-containing NMDARs show a decrease in peak amplitude. Both peak amplitude and desensitization effects of HCY can be occluded by saturating the NMDAR with glycine. Since glycine concentrations are not saturating in the brain, HCY could play an NMDAR-modulating role in the nervous system. We also show that HCY shares characteristics with glutamate and suggest that HCY affects both the agonist and coagonist site of the NMDAR.

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Section: Hcy Effect On Nmdar Currents Depends On Glun2 Subunit Compmentioning

confidence: 99%

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

Bolton

Phillips

Constantine‐Paton

2013

Journal of Neurophysiology

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“…Further, GLYT1 transporters may function in either the forward or reverse direction depending upon astrocytic membrane potential, and may therefore dynamically regulate extracellular glycine levels. 31 System A transporters are expressed in both neurons and glia, and transport a range of small neutral amino acids (eg, glutamine, proline, serine) along with glycine. The role of System A transporters in glycine homeostasis is still under evaluation.…”

Section: Modulatory Sitesmentioning

confidence: 99%

Glutamate as a therapeutic target in psychiatric disorders

2004

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Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic neurotransmission may be modulated at multiple levels, only a minority of which are currently being exploited for pharmaceutical development. Ionotropic receptors for glutamate are divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of the NMDAR is currently a favored therapeutic target, with several modulatory agents currently undergoing clinical development. Of these, the full agonists glycine and D-serine have both shown to induce significant, large effect size reductions in persistent negative and cognitive symptoms when added to traditional or newer atypical antipsychotics in double-blind, placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine. Brain transporters for D-serine have recently been described. Metabotropic glutamate receptors are positively (Group I) or negatively (Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders. Other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD. Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Approximately 60% of neurons in the brain, including all cortical pyramidal neurons and thalamic relay neurons, utilize glutamate as their primary neurotransmitter. 1 As a result, virtually all thalamocortical, corticocortical and corticofugal neurotransmission in the brain is mediated by glutamate. Glutamate is released from presynaptic terminals in response to neuronal depolarization, and is recycled by excitatory amino acid (EAA) transporters located on both neurons and glia. 2 Within glia, glutamate is converted to glutamine and released into extracellular fluid from which it is reabsorbed into presynaptic terminals and converted back to glutamate via action of neuronal glutaminase. Up to 2/3 of brain energy metabolism is related to reuptake and recycling of glutamate. 3 As such, functional imaging modalities, such as PET and fMRI, indexing activity primarily of brain glutamatergic systems. 4 The exchange of glutamine from glia to neurons is accomplished by coordinated actions of two transport systems, systems N and A, both of which are members of sodium-dependent neutral amino acid (SNAT) family of transporters. 5 These transport systems also transport precursors for cysteine and glycine, which are precursors to glutathione synthesis. 6 As these transporters are electrogenic, glutamate transporters may also participate in cellular signaling. 7 As with glutamate and GABA transporters, these recycling systems may constitute interesti...

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“…Indeed, targeted disruption of the dopamine transporter gene in mice drastically reduces brain dopamine storage and release (Giros et al, 1996;Jones et al, 1998). Related neuronal transporters for monoamines, GABA and glycine apparently have a similar role in transmitter recycling (Roux and Supplisson, 2000). However, the plasma membrane transporters for glutamate belong to a distinct family of proteins (Kanai and Hediger, 1992;Pines et al, 1992;Storck et al, 1992) that generally reside either on astrocytes or, if expressed by neurons, are postsynaptic rather than on the nerve terminal (Rothstein et al, 1994;Chaudhry et al, 1995).…”

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confidence: 99%

Glutamine Uptake by Neurons: Interaction of Protons with System A Transporters

et al. 2002

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Astrocytes provide the glutamine required by neurons to synthesize glutamate and GABA. However, the mechanisms involved in glutamine transfer from glia to neurons have remained poorly understood. Recent work has implicated the System N transporter SN1 in the efflux of glutamine from astrocytes and the very closely related System A transporters SA1 and SA2 in glutamine uptake by neurons. To understand how these closely related proteins mediate flux in different directions, we have examined their ionic coupling. In contrast to the electroneutral exchange of H ϩ for Na ϩ and neutral amino acid catalyzed by SN1, we now show that SA1 and SA2 do not couple H ϩ movement to amino acid flux. As a result, SA1 and SA2 are electrogenic and do not mediate flux reversal as readily as SN1. Differences between System N and A transporters in coupling to H ϩ thus contribute to the delivery of glutamine from glia to neurons. Nonetheless, although they are not transported, H ϩ inhibit SA1 and SA2 by competing with Na ϩ .

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Neuronal and Glial Glycine Transporters Have Different Stoichiometries

Cited by 249 publications

References 50 publications

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

Glutamate as a therapeutic target in psychiatric disorders

Glutamine Uptake by Neurons: Interaction of Protons with System A Transporters

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