Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • The glycine receptor is an

    2022-09-28

    The glycine receptor is an ionotropic neurotransmitter receptor coupled to a chloride ion channel. Glycine receptors are typically described as inhibitory and distributed in the spinal cord and brainstem, though mRNA transcription labelling studies in rats show expression in the hippocampus, cingulate and entorhinal neocortex. Reduced GlyR inhibition causes hyperekplexia in animals. The clinical course of our patient and correlation with titres suggests that GlyR Ab titre may have risen following a possible infective trigger and fell following treatment with first-line immunotherapy including pulsed steroids and intravenous immunoglobulins (Fig. 1). GlyR Ab titre may correlate with the dyskinesia but not necessarily with the seizures, which in this patient appeared well controlled with anticonvulsants. This is in contrast to FBDS which is typically anticonvulsant-resistant, has a high adverse reaction rate, but responds very promptly to steroids and immunotherapy. The clinical course of our patient was monophasic, but it is possible that chronic impairment could have resulted had immunotherapy not been instituted. Seizures were prominent in this patient at the onset of his illness. Seizures are a common feature in children and are beginning to be associated with Finasteride to NMDARs or VGKC complexes.7, 15 The inhibitory nature of glycine receptors and their distribution in the spinal cord and brainstem might possibly lead to a brainstem release phenomenon, resulting in seizures. While it is possible that the seizures in this patient might represent acute symptomatic seizures related to Parainfluenza 3 pharyngitis, the recurrence of seizures almost 3 weeks later make this less likely. Viral infections may be the trigger for autoimmune activation and have been shown to be associated with NMDAR and D2R antibodies in the case of herpes simplex virus (HSV).16, 17 Unfortunately in this patient, CSF was not available for testing. The absence of CSF testing for NMDAR and Gly-R is a weakness and the concurrent presence of two autoantibodies cannot be excluded. A broader panel of autoantibodies beyond GlyR, NMDAR and VGKC would have helped elucidate the immunological characteristics of this patient and should be considered in future patients.
    Conflict of interest statement
    Introduction N-methyl-d-aspartate (NMDA) receptors operate as obligate heterotetramers that usually contain two GluN1 subunits and either two GluN2 subunits or one GluN2 and one GluN3 subunit [1]. While GluN1 and GluN3 bind glycine and d-serine, GluN2 binds glutamate; hence, activation of GluN2-containing receptors requires both glycine/d-serine and glutamate. In contrast, receptors composed of GluN1 and GluN3 subunits can be activated by glycine in the absence of glutamate [2], [3]. These GluN1/GluN3 excitatory glycine receptors also lack the high Ca2+ permeability and strong voltage-dependent Mg2+ block shown by conventional GluN2-containing NMDA receptors [2], [4]. We have recently used atomic force microscopy (AFM) imaging of GluN1/GluN2A NMDA receptors integrated into lipid bilayers to reveal a rapid activation-induced conformational change in the extracellular domain of the receptor [5]. In the present study, we have isolated receptors composed of GluN1 and GluN3A subunits. We show that the GluN1/GluN3 receptor undergoes a conformational change in response to either glycine or d-serine alone, but does not respond to glutamate.
    Materials and methods
    Results An in situ proximity ligation assay was carried out to determine whether GluN1 and GluN3A interact in intact tsA 201 cells. Cells were co-transfected with DNA encoding GluN1-HA/His8 and WT GluN3A. The assay uses two secondary antibodies, each bearing a short DNA strand [8]. When the secondary antibodies are brought into close proximity (<40nm) by binding to their relevant primary antibodies (in this case rabbit anti-HA and a mouse anti-GluN3A that recognizes the extracellular loop between transmembrane regions 3 and 4), the DNA strands hybridize with an additional circle-forming oligodeoxynucleotide. Ligation then creates a complete circularized oligodeoxynucleotide, and rolling circle amplification increases the amount of circular DNA several 100-fold. The DNA is then visualized using a fluorescent probe. The assay gave a bright signal with cells co-expressing GluN1-HA/His8 and GluN3A (Fig. 1A); however, there was no signal when the anti-GluN3A antibody was replaced by a mouse anti-V5 antibody (Fig. 1B), even though the cell monolayer was almost confluent, as can be seen in the corresponding brightfield image (Fig. 1C). Hence, GluN1 interacts with GluN3A within intact cells.