Subunit-specific modulation of glycine receptors by neurosteroids

Maksay, Gábor; Laube, Bodo; Betz, Heinrich

doi:10.1016/s0028-3908(01)00071-5

Cited by 77 publications

(50 citation statements)

References 38 publications

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“…Potencies have been published for pregnenolone sulfate and progesterone in chick embryonic spinal cord (531,532) and Xenopus laevis oocytes (275). Maksay et al (275) also report on effects of DHEAS.…”

Section: Neurosteroidsmentioning

confidence: 99%

“…Neuroactive steroids do seem to possess stereoselectivity at carbon 3. On the other hand, strict structural requirements of the 3-substituents for potentiation versus inhibition of glycine receptor chloride channel function were demonstrated (275). It has been hypothesized that these data advocate a role for neuroactive steroids in neuronal development, since the subunit-specific effects are particularly pronounced in receptors that most closely resemble perinatal glycine receptor composition (275).…”

Section: Neurosteroidsmentioning

confidence: 99%

See 1 more Smart Citation

Nongenomic Steroid Action: Controversies, Questions, and Answers

Lösel

Falkenstein

Feuring

et al. 2003

Physiological Reviews

500

321

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Lösel, Ralf M., Elisabeth Falkenstein, Martin Feuring, Armin Schultz, Hanns-Christian Tillmann, Karin Rossol-Haseroth, and Martin Wehling. Nongenomic Steroid Action: Controversies, Questions, and Answers. Physiol Rev 83: 965–1016, 2003; 10.1152/physrev.00003.2003.—Steroids may exert their action in living cells by several ways: 1) the well-known genomic pathway, involving hormone binding to cytosolic (classic) receptors and subsequent modulation of gene expression followed by protein synthesis. 2) Alternatively, pathways are operating that do not act on the genome, therefore indicating nongenomic action. Although it is comparatively easy to confirm the nongenomic nature of a particular phenomenon observed, e.g., by using inhibitors of transcription or translation, considerable controversy exists about the identity of receptors that mediate these responses. Many different approaches have been employed to answer this question, including pharmacology, knock-out animals, and numerous biochemical studies. Evidence is presented for and against both the participation of classic receptors, or proteins closely related to them, as well as for the involvement of yet poorly understood, novel membrane steroid receptors. In addition, clinical implications for a wide array of nongenomic steroid actions are outlined.

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Section: Neurosteroidsmentioning

confidence: 99%

Section: Neurosteroidsmentioning

confidence: 99%

Nongenomic Steroid Action: Controversies, Questions, and Answers

Lösel

Falkenstein

Feuring

et al. 2003

Physiological Reviews

500

321

View full text Add to dashboard Cite

show abstract

“…Ionotropic glycine receptors, which like GABA A receptors are ligand-gated chloride channels, are sensitive to some neuroactive steroids, although again the structure-activity relationship is different, and steroid effects on glycine receptors exhibit more subunit-dependent differences than GABA A receptors (Maksay et al, 2001). Some GABA-potentiating steroids, including endogenous GABA-potentiating steroids, were reported to be largely inactive at glycine receptors Belelli et al, 1999b;Harrison et al, 1987;Pistis et al, 1997).…”

Section: C Actions Of Neurosteroids Not Involving Gaba a Receptorsmentioning

confidence: 99%

“…Recent papers, however, reported significant antagonistic effects of 3α5βP on native and recombinant glycine receptors (Jiang et al, 2006;Weir et al, 2004). Also, sulfated steroids antagonize glycine receptors (Maksay et al, 2001;Wu et al, 1997), and pregnenolone potentiates glycine receptors in a subunit-specific manner (Maksay et al, 2001). Finally, progesterone inhibits glycine receptors, but by a mechanism apparently different than the sulfated steroids.…”

Section: C Actions Of Neurosteroids Not Involving Gaba a Receptorsmentioning

confidence: 99%

Mechanisms of neurosteroid interactions with GABAA receptors

Akk¹,

Covey²,

Evers³

et al. 2007

Pharmacology & Therapeutics

142

166

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Neuroactive steroids have some of their most potent actions by augmenting the function of GABA A receptors. Endogenous steroid actions on GABA A receptors may underlie important effects on mood and behavior. Exogenous neuroactive steroids have potential as anesthetics, anticonvulsants, and neuroprotectants. We have taken multiple approaches to understand more completely the interaction of neuroactive steroids with GABA A receptors. We have developed many novel steroid analogues in this effort. Recent work has resulted in synthesis of new enantiomer analogue pairs, novel ligands that probe various properties of the steroid pharmacophore, fluorescent neuroactive steroid analogues, and photoaffinity labels. Using these tools, combined with receptor binding and electrophysiological assays, we have begun to untangle the complexity of steroid actions at this important class of ligand-gated ion channel.

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“…For instance, single-channel studies showed that the opening probability of ␣ 2 GlyRs was very low after a fast application of glycine, suggesting that they cannot be activated by fast neurotransmitter release at synapses (11). Similarly, other electrophysiological studies have reported that ␣ GlyR isoforms possess different sensitivities to allosteric regulators, such as neurosteroids, zinc ions, and ethanol (12)(13)(14). These studies, in agreement with others in cultured spinal neurons and hypoglossal motoneuron slices (15)(16), showed that receptors comprising ␣ 1 are more sensitive to ethanol than those containing ␣ 2 subunits (12).…”

mentioning

confidence: 99%

Molecular Requirements for Ethanol Differential Allosteric Modulation of Glycine Receptors Based on Selective Gβγ Modulation

Yévenes

Moraga-Cid

Ávila

et al. 2010

Journal of Biological Chemistry

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It is now believed that the allosteric modulation produced by ethanol in glycine receptors (GlyRs) depends on alcohol binding to discrete sites within the protein structure. Thus, the differential ethanol sensitivity of diverse GlyR isoforms and mutants was explained by the presence of specific residues in putative alcohol pockets. Here, we demonstrate that ethanol sensitivity in two ligand-gated ion receptor members, the GlyR adult ␣ 1 and embryonic ␣ 2 subunits, can be modified through selective mutations that rescued or impaired G␤␥ modulation. Even though both isoforms were able to physically interact with G␤␥, only the ␣ 1 GlyR was functionally modulated by G␤␥ and pharmacological ethanol concentrations. Remarkably, the simultaneous switching of two transmembrane and a single extracellular residue in ␣ 2 GlyRs was enough to generate GlyRs modulated by G␤␥ and low ethanol concentrations. Interestingly, although we found that these TM residues were different to those in the alcohol binding site, the extracellular residue was recently implicated in conformational changes important to generate a preopen-activated state that precedes ion channel gating. Thus, these results support the idea that the differential ethanol sensitivity of these two GlyR isoforms rests on conformational changes in transmembrane and extracellular residues within the ion channel structure rather than in differences in alcohol binding pockets. Our results describe the molecular basis for the differential ethanol sensitivity of two ligand-gated ion receptor members based on selective G␤␥ modulation and provide a new mechanistic framework for allosteric modulations of abuse drugs.Glycine receptors (GlyRs) 4 are members of the ligand-gated ion receptor (LGIC) superfamily, which includes the Cys-loop family composed of the inhibitory ␥-aminobutyric acid receptors and GlyRs and the excitatory nicotinic acetylcholine (nAChR) and 5-hydroxytryptamine receptors. These ionotropic receptors mediate fast synaptic transmission in the central nervous system (1, 2). Specifically, inhibitory GlyRs are critical for the control of excitability in the mammalian spinal cord and brain stem, regulating important physiological functions such as pain transmission, respiratory rhythms, motor coordination, and neuronal development (3-7).Like all Cys-loop receptors, GlyRs are heteropentameric complexes composed of ␣ and ␤ subunits, which can assemble to form homomeric (5␣) or heteromeric (2␣3␤) channels. To date, molecular cloning studies have demonstrated four isoforms of the ␣ GlyRs (␣ 1-4 ) and one ␤ isoform. Homomeric and heteromeric receptors share most of the GlyR general features, including a high percentage of identity between ␣ GlyRs (Ϸ75%). Nevertheless, biochemical, immunocytochemical, and in situ hybridization studies have shown that the expression of the subunits are developmentally and regionally regulated (3,4,8). For example, the ␣ 1 subunit expression increases after birth, whereas expression of the ␣ 2 subunit appears mainly restricted to early...

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Subunit-specific modulation of glycine receptors by neurosteroids

Cited by 77 publications

References 38 publications

Nongenomic Steroid Action: Controversies, Questions, and Answers

Nongenomic Steroid Action: Controversies, Questions, and Answers

Mechanisms of neurosteroid interactions with GABAA receptors

Molecular Requirements for Ethanol Differential Allosteric Modulation of Glycine Receptors Based on Selective Gβγ Modulation

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