Characterization of the subunit composition and structure of adult human glycine receptors

Yu, Hailong; Bai, Xiao Chen; Wang, Weiwei

doi:10.1016/j.neuron.2021.08.019

Cited by 38 publications

(66 citation statements)

References 82 publications

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“…Although there is evidence for the existence of GlyRα homomeric receptors, α/β hetero-oligomers prevail in the ventral spinal cord during adulthood (Becker et al, 1988 ; Langosch et al, 1988 ). The subunit composition, however, is still controversially discussed ranging between a 2α3β stoichiometry to a 4α1β (Grudzinska et al, 2005 ; Yu et al, 2021 ). To date, four α subunits (α1–4) and one β subunit are known, all of which are expressed in the rodent spinal cord, but only the α subunits α1- α3 and the β subunit are being expressed in humans (Dutertre et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Nociception in the Glycine Receptor Deficient Mutant Mouse Spastic

Groemer

Triller

Zeilhofer

et al. 2022

Front. Mol. Neurosci.

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Glycine receptors (GlyRs) are the primary mediators of fast inhibitory transmission in the mammalian spinal cord, where they modulate sensory and motor signaling. Mutations in GlyR genes as well as some other genes underlie the hereditary disorder hyperekplexia, characterized by episodic muscle stiffness and exaggerated startle responses. Here, we have investigated pain-related behavior and GlyR expression in the spinal cord of the GlyR deficient mutant mouse spastic (spa). In spastic mice, the GlyR number is reduced due to a β subunit gene (Glrb) mutation resulting in aberrant splicing of GlyRβ transcripts. Via direct physical interaction with the GlyR anchoring protein gephyrin, this subunit is crucially involved in the postsynaptic clustering of heteromeric GlyRs. We show that the mutation differentially affects aspects of the pain-related behavior of homozygous Glrbspa/Glrbspa mice. While response latencies to noxious heat were unchanged, chemically induced pain-related behavior revealed a reduction of the licking time and an increase in flinching in spastic homozygotes during both phases of the formalin test. Mechanically induced nocifensive behavior was reduced in spastic mice, although hind paw inflammation (by zymosan) resulted in allodynia comparable to wild-type mice. Immunohistochemical staining of the spinal cord revealed a massive reduction of dotted GlyRα subunit immunoreactivity in both ventral and dorsal horns, suggesting a reduction of clustered receptors at synaptic sites. Transcripts for all GlyRα subunit variants, however, were not reduced throughout the dorsal horn of spastic mice. These findings suggest that the loss of functional GlyRβ subunits and hence synaptically localized GlyRs compromises sensory processing differentially, depending on stimulus modality.

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Section: Introductionmentioning

confidence: 99%

Nociception in the Glycine Receptor Deficient Mutant Mouse Spastic

Groemer

Triller

Zeilhofer

et al. 2022

Front. Mol. Neurosci.

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“…The β Subunit Converts α2 Subunits to an "α1-Like" Glycine Receptor With Respect to Ethanol Sensitivity Glycine receptors can be expressed in recombinant systems as homomeric or heteromeric complexes (4 α subunits:1 β subunit) (Yu et al, 2021;Zhu and Gouaux, 2021) and their expression can be monitored looking at changes on their properties such as time to activation and glycine affinity (Figure 1A). Figure 1B shows current traces activated by an EC 10 concentration of glycine in homomeric and heteromeric GlyRs.…”

Section: Resultsmentioning

confidence: 99%

Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors

Muñoz

Mariqueo

Murath

et al. 2021

Front. Mol. Neurosci.

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Alpha1-containing glycine receptors (GlyRs) are major mediators of synaptic inhibition in the spinal cord and brain stem. Recent studies reported the presence of α2-containing GlyRs in other brain regions, such as nucleus accumbens and cerebral cortex. GlyR activation decreases neuronal excitability associated with sensorial information, motor control, and respiratory functions; all of which are significantly altered during ethanol intoxication. We evaluated the role of β GlyR subunits and of two basic amino acid residues, K389 and R390, located in the large intracellular loop (IL) of the α2 GlyR subunit, which are important for binding and functional modulation by Gβγ, the dimer of the trimeric G protein conformation, using HEK-293 transfected cells combined with patch clamp electrophysiology. We demonstrate a new modulatory role of the β subunit on ethanol sensitivity of α2 subunits. Specifically, we found a differential allosteric modulation in homomeric α2 GlyRs compared with the α2β heteromeric conformation. Indeed, while α2 was insensitive, α2β GlyRs were substantially potentiated by ethanol, GTP-γ-S, propofol, Zn2+ and trichloroethanol. Furthermore, a Gβγ scavenger (ct-GRK2) selectively attenuated the effects of ethanol on recombinant α2β GlyRs. Mutations in an α2 GlyR co-expressed with the β subunit (α2AAβ) specifically blocked ethanol sensitivity, but not propofol potentiation. These results show a selective mechanism for low ethanol concentration effects on homomeric and heteromeric conformations of α2 GlyRs and provide a new mechanism for ethanol pharmacology, which is relevant to upper brain regions where α2 GlyRs are abundantly expressed.

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“…GlyR-Abs was firstly reported to be related to PERM in 2008 by Hutchinson et al ( 2 ), and they were most frequently found in patients with PERM ( 3 ). Glycine receptors are pentameric ligand-gated chloride channels present mainly in the adult brainstem and spinal cord, facilitating inhibitory signaling, and the stoichiometry has been recently proved to be 4 alpha: 1 beta subunits ( 4 ). Mutations of GlyRα1 result in hereditary hyperekplexia, a disorder characterized by excessive startle responses in infancy, which resembles the phenotype of PERM ( 5 ).…”

Section: Discussionmentioning

confidence: 99%

Facial Palsy as Initial Symptom in Glycine Receptor Antibody Positive Progressive Encephalomyelitis With Rigidity and Myoclonus: A Case Report

Wang

Zhang

et al. 2022

Front. Neurol.

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Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare and disabling syndrome characterized by painful spasms, myoclonic jerks, hyperekplexia, brainstem signs, and dysautonomia, which is considered to be a severe form of stiff person spectrum disorder (SPSD) and is mostly associated with glycine receptor antibodies. The PERM has an acute or subacute course, with complex and varied initial symptoms mainly manifest as stiffness and pain. The authors present the case of a male patient admitted for intractable stiffness and paroxysmal myoclonus of the lower extremities preceded by a 5-day history of facial weakness. After admission, his symptoms deteriorated rapidly. He developed progressive generalized hypertonia and painful spasms, which quickly spread to the upper extremities, and he suffered frequent paroxysmal myoclonus. Serum and cerebrospinal fluid (CSF) were tested by a cell-based assay, and both were positive for glycine receptor antibodies (GlyR-Abs). The patient developed complications, such as crushed teeth, lumbar vertebral compression fractures, and psoas major muscle abscess, during rapid disease progression, although he responded well after being treated with intravenous methylprednisolone and immunoglobulin. This report of PERM, initiated as facial palsy followed by acute progression, helps to expand the clinical spectrum of this rare autoimmune disorder and raise awareness of the prevention of complications.

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Characterization of the subunit composition and structure of adult human glycine receptors

Cited by 38 publications

References 82 publications

Nociception in the Glycine Receptor Deficient Mutant Mouse Spastic

Nociception in the Glycine Receptor Deficient Mutant Mouse Spastic

Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors

Facial Palsy as Initial Symptom in Glycine Receptor Antibody Positive Progressive Encephalomyelitis With Rigidity and Myoclonus: A Case Report

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