Inhibitors of GlyT1 and GlyT2 differentially modulate inhibitory transmission

  title={Inhibitors of GlyT1 and GlyT2 differentially modulate inhibitory transmission},
  author={Tai-Xiang Xu and Neng Gong and Tian-Le Xu},
The chronic effects of glycine transporter 1 and 2 inhibitors (sarcosine and ALX-1393, respectively) on miniature inhibitory postsynaptic currents were studied in cultured spinal neurons. We found that sarcosine increased the frequency of overall miniature inhibitory postsynaptic currents without affecting the ratio of glycinergic, mixed and GABAergic miniature inhibitory postsynaptic currents, whereas ALX-1393 changed the ratio by increasing the proportions of GABAergic and mixed miniature… 

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

Recent advances in understanding the role of GlyT2 in the pathophysiology of inhibitory glycinergic neurotransmission are reviewed, with a focus on the areas of caudal areas of the nervous system and pain transmission.

Spinal Antiallodynia Action of Glycine Transporter Inhibitors in Neuropathic Pain Models in Mice

GlyTs were established as the target molecules for the development of medicaments for neuropathic pain after it was demonstrated that i.v. or intrathecal administration of GlyT1 inhibitors, or knockdown of spinal GlyTs by small interfering RNA of GlyTs mRNA produced a profound antiallodynia effect in a partial peripheral nerve ligation model and other neuropathicPain models in mice.

Glycine and glycine receptor signaling in hippocampal neurons: Diversity, function and regulation

Molecular Basis for Substrate Discrimination by Glycine Transporters*

It is demonstrated that the LeuTAa structure represents a good working model of the Na+/Cl--dependent neurotransmitters and that differences in substrate selectivity can be attributed to a single difference of a glycine residue in transmembrane domain 6 of GLYT1 for a serine residue at the corresponding position ofGLYT2.

Blockade of glycine transporter (GlyT) 2, but not GlyT1, ameliorates dynamic and static mechanical allodynia in mice with herpetic or postherpetic pain.

The results suggest that GlyT2 is a potential target for treatment of dynamic and static allodynia in patients with herpes zoster and postherpetic neuralgia and the lack of efficacy of GlyT1 inhibitor may be explained by activation of NMDA receptors and the down-regulation ofglyT1 in the lumbar dorsal horn.

Glycine receptors support excitatory neurotransmitter release in developing mouse visual cortex

These results define mechanisms that contribute to baseline neurotransmission during critical periods of neuronal development, and help identify synaptic functions that could be impacted by GlyR dysfunction.

Development of an N-Acyl Amino Acid That Selectively Inhibits the Glycine Transporter 2 To Produce Analgesia in a Rat Model of Chronic Pain.

It is demonstrated that 33 provides greater analgesia at lower doses, and does not possess the severe side effects of the very slowly reversible GlyT2 inhibitor, ORG25543 (2).



Structure, function and regulation of glycine neurotransporters.

The glycinergic inhibitory synapse

  • P. Legendre
  • Biology
    Cellular and Molecular Life Sciences CMLS
  • 2001
Recent work on glycine receptor channels and the synapses at which they mediate inhibitory signalling in both young and adult animals necessitates an update of the vision of glycinergic inhibitory transmission.

Role of glial and neuronal glycine transporters in the control of glycinergic and glutamatergic synaptic transmission in lamina X of the rat spinal cord

Blocking glial and/or neuronal glycine transporters increased the level of glycine in spinal cord slices, which in turn prolonged the duration of glycinergic synaptic current and potentiated the NMDA‐mediated synaptic response.

Modulation of glycinergic synaptic current kinetics by octanol in mouse hypoglossal motoneurons

The data show that octanol prolongs the decay time course of glycinergic synaptic currents by mechanisms independent of glycine uptake or intracellular acidification, and conclude that the effects were most probably due to direct action on postsynaptic glycine receptors.

Presynaptic glycine receptors enhance transmitter release at a mammalian central synapse

Evidence is reported for presynaptic ionotropic glycine receptors, using pre- and postsynaptic recordings of a calyceal synapse in the medial nucleus of the trapezoid body (MNTB), which reveals a novel site of action of the transmitter glycine, and indicates that under certain conditions presynptic Cl- channels may increase transmitter release.

Presence of the vesicular inhibitory amino acid transporter in GABAergic and glycinergic synaptic terminal boutons.

Data support the view of a common vesicular transporter for these two inhibitory transmitters, which would be responsible for their costorage in the same synaptic vesicle and subsequent corelease at mixed GABA-and-glycine synapses.

Glycine potentiates the NMDA response in cultured mouse brain neurons

G glycine may facilitate excitatory transmission in the brain through an allosteric activation of the NMDA receptor, and can be observed in outside-out patches as an increase in the frequency of opening of the channels activated by NMDA agonists.

Colocalization of GABA, glycine, and their receptors at synapses in the rat spinal cord

The results strongly support the idea that cotransmission by GABA and glycine occurs in the spinal cord.

Glycine transporters are differentially expressed among CNS cells

Immunoblots show that GLYT1 is expressed at the highest concentrations in the spinal cord, brainstem, diencephalon, and retina, and, in a lesser degree, to the olfactory bulb and brain hemispheres, whereas it is not detected in peripheral tissues.