A single amino acid exchange alters the pharmacology of neonatal rat glycine receptor subunit

Kuhse, Jochen; Schmieden, Volker; Betz, Heinrich

doi:10.1016/0896-6273(90)90346-h

Cited by 185 publications

(128 citation statements)

References 27 publications

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“…GlyR α2-mediated currents in response to taurine have been implicated in the differentiation of cortical and retinal (56) neurons; however, the analysis of Glra2 −/Y mice failed to reveal retinal or cortical abnormalities (54). Notably, the GlyR α subunits expressed in brain respond differently to taurine and β-alanine, such that these amino acids have little to no efficacy at homomeric α2 or α3 GlyRs but do activate α1 GlyRs, albeit with less efficacy and potency than glycine (57,58). Our data showing that α3 GlyRs mediate tonic currents in brain suggest that glycine itself probably serves as the main endogenous GlyR ligand in the forebrain.…”

Section: Discussionmentioning

confidence: 98%

Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain

McCracken

Lowes

Salling

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Neuronal inhibition can occur via synaptic mechanisms or through tonic activation of extrasynaptic receptors. In spinal cord, glycine mediates synaptic inhibition through the activation of heteromeric glycine receptors (GlyRs) composed primarily of α1 and β subunits. Inhibitory GlyRs are also found throughout the brain, where GlyR α2 and α3 subunit expression exceeds that of α1, particularly in forebrain structures, and coassembly of these α subunits with the β subunit appears to occur to a lesser extent than in spinal cord. Here, we analyzed GlyR currents in several regions of the adolescent mouse forebrain (striatum, prefrontal cortex, hippocampus, amygdala, and bed nucleus of the stria terminalis). Our results show ubiquitous expression of GlyRs that mediate large-amplitude currents in response to exogenously applied glycine in these forebrain structures. Additionally, tonic inward currents were also detected, but only in the striatum, hippocampus, and prefrontal cortex (PFC). These tonic currents were sensitive to both strychnine and picrotoxin, indicating that they are mediated by extrasynaptic homomeric GlyRs. Recordings from mice deficient in the GlyR α3 subunit (Glra3 −/− ) revealed a lack of tonic GlyR currents in the striatum and the PFC. In Glra2 −/Y animals, GlyR tonic currents were preserved; however, the amplitudes of current responses to exogenous glycine were significantly reduced. We conclude that functional α2 and α3 GlyRs are present in various regions of the forebrain and that α3 GlyRs specifically participate in tonic inhibition in the striatum and PFC. Our findings suggest roles for glycine in regulating neuronal excitability in the forebrain.glycine receptor | tonic inhibition | Cys-loop receptor | strychnine | alpha subunits

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Section: Discussionmentioning

confidence: 98%

Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain

McCracken

Lowes

Salling

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Striata and SN of six rats were pooled for RNA extraction. RNA was extracted from the frozen tissues as described by Chomczynski & Sacchi (1987) (Grenningloh et al, 1987;Kuhse et al, 1990 DOPAC and HVA averaged 20 ± 1.6, 22 + 2 and 26 ±0.5% (n = 6). Applying these recoveries, and correcting for the volume of preservative (15 jil added to 30 fLI of microdialysate), estimated extracellular fluid concentrations of dopamine, DOPAC, and HVA were 0.10 ± 0.004, 17.8 ± 0.9, and 5.7 ± 0.6ymol 1'.…”

Section: Transcription Ofgenes Encoding For Glycine Receptorsmentioning

confidence: 99%

Glycine stimulates striatal dopamine release in conscious rats

Yadid

Pacák

Golomb

et al. 1993

British J Pharmacology

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1 Glycine is an inhibitory neurotransmitter in the spinal cord and brainstem. The mechanism of this inhibition is via binding of glycine to specific receptors, increasing transmembrane Cl-conductance and hyperpolarizing neurones. Strychnine selectively antagonizes these effects. The role of glycinergic neurones in supraspinal regions is poorly understood. 2 Effects of glycine on release of catecholamines in the striatum were examined by microdialysis in freely-moving rats. Transcription of the genes encoding strychnine-sensitive glycine receptors was assessed in the striatum and substantia nigra, by use of reverse transcription followed by the polymerase chain reaction. 3 Glycine administered via the microdialysis probe dose-dependently increased concentrations of dopamine and its metabolites, dihydroxyphenylacetic acid and homovanillic acid, in the perfusate, indicating increased local release and metabolism of dopamine. Strychnine markedly attenuated these responses. Whereas striatal tissue did not contain mRNA for either the adult or neonatal form of strychnine-sensitive glycine receptor, nigral tissue contained a message for the adult form. 4 The results suggest that dopaminergic cells in the substantia nigra synthesize strychnine-sensitive glycine receptors and transport the receptors to terminals in the striatum. Occupation of the glycine receptors then exerts a net stimulatory effect on striatal dopamine release in vivo.

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“…Presently three a subunit variants, c+a3, have been characterized in detail [15-181, which all form glycine-gated chloride channels upon heterologous expression in Xerropus oocytes [16][17][18][19] or mammalian cell lines [20]. The pharmacology of these homooligomeric GlyRs is very similar to that found for in vivo receptors; however, higher agonist *Present address: Department of Physiology, Kanagawa Dental College, Yokosuka, Japan.…”

Section: Introductionmentioning

confidence: 99%

“…concentrations are required for channel gating. Moreover, in case of neonatal GlyRs, which contain cr, as the ligand binding subunit [17], significant differences in sensitivity to the glycinergic antagonist strychnine have been revealed by biochemical, electrophysiological and heterologous expression experiments [2,14,16,17]. These discrepancies may relate to the lack of additional subunits [3,5].…”

Section: Introductionmentioning

confidence: 99%

Coexpression of the receptor‐associated protein gephyrin changes the ligand binding affinities of α₂ glycine receptors

et al. 1992

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The inhibitory glycine receptor (GlyR) is a ligandagated chloride channel protein, whose ligand binding a subunit occurs in several isoforrns in the mammalian centrdl nervous system. Here we show that coexpression of the GlyR-associated protein gephyrin changes the agonist and antagonist binding affinities of GlyRs generated by a2 subunit expression in 293 kidney cells, Thus, a receptor-associated protein modifies the functional properties of a neurotransmitter receptor, This may contribute to an optimization of the postsynaptic neurotransmitter response.

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A single amino acid exchange alters the pharmacology of neonatal rat glycine receptor subunit

Cited by 185 publications

References 27 publications

Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain

Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain

Glycine stimulates striatal dopamine release in conscious rats

Coexpression of the receptor‐associated protein gephyrin changes the ligand binding affinities of α₂ glycine receptors

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A single amino acid exchange alters the pharmacology of neonatal rat glycine receptor subunit

Cited by 185 publications

References 27 publications

Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain

Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain

Glycine stimulates striatal dopamine release in conscious rats

Coexpression of the receptor&#x2010;associated protein gephyrin changes the ligand binding affinities of α2 glycine receptors

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Coexpression of the receptor‐associated protein gephyrin changes the ligand binding affinities of α₂ glycine receptors