The mechanism of the negative impact of corticosteroids on the induction and progress of mental illness remains unclear. In this work, we studied the effects of corticosteroids on the activity of neuronal glycine receptors (GlyR) and GABA-A receptors (GABAAR) by measuring the chloride current induced by the application of GABA (2 or 5 μM) to isolated cerebellar Purkinje cells (IGABA) and by the application of glycine (100 μM) to pyramidal neurons of the rat hippocampus (IGly). It was found that corticosterone, 5α-dihydrodeoxycorticosterone, allotetrahydrocorticosterone, cortisol, and 17α,21-dihydroxypregnenolone were able to accelerate the desensitization of the IGly at physiological concentrations (IC50 values varying from 0.39 to 0.72 μM). Next, cortisone, 11-deoxycortisol, 11-deoxycorticosterone, 5β-dihydrodeoxycorticosterone, and tetrahydrocorticosterone accelerated the desensitization of IGly with IC50 values varying from 10.3 to 15.2 μM. Allotetrahydrocorticosterone and tetrahydrocorticosterone potentiated the IGABA albeit with high EC50 values (18-23 μM). The rest of the steroids had no effect on IGABA in the range of concentrations of 1-100 μM. Finally, our study has suggested a structural relationship of the 3β-hydroxyl group/3-oxo group with the selective modulatory activity on GlyRs in contrast to the 3α-hydroxyl group that is pivotal for GABAARs. In summary, our results suggest that increased GlyR desensitization by corticosteroids may contribute to brain dysfunction under chronic stress and identify corticosteroids for further development as selective modulators of GlyRs.
- MeSH
- GABA farmakologie MeSH
- glycin * farmakologie MeSH
- hormony kůry nadledvin farmakologie MeSH
- krysa rodu rattus MeSH
- neurony MeSH
- receptory GABA-A MeSH
- receptory glycinu * fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Inhibitory circuits in the auditory brainstem undergo multiple postnatal changes that are both activity-dependent and activity-independent. We tested to see if the shift from GABA- to glycinergic transmission, which occurs in the rat medial nucleus of the trapezoid body (MNTB) around the onset of hearing, depends on sound-evoked neuronal activity. We prevented the activity by bilateral cochlear ablations in early postnatal rats and studied ionotropic GABA and glycine receptors in MNTB neurons after hearing onset. The removal of the cochlea decreased responses of GABAA and glycine receptors to exogenous agonists as well as the amplitudes of inhibitory postsynaptic currents. The reduction was accompanied by a decrease in the number of glycine receptor- or vesicular GABA transporter-immunopositive puncta. Furthermore, the ablations markedly affected the switch in presynaptic GABAA to glycine receptors. The increase in the expression of postsynaptic glycine receptors and the shift in inhibitory transmitters were not prevented. The results suggest that inhibitory transmission in the MNTB is subject to multiple developmental signals and support the idea that auditory experience plays a role in the maturation of the brainstem glycinergic circuits.
- MeSH
- ablace * MeSH
- corpus trapezoideum fyziologie MeSH
- inhibiční postsynaptické potenciály fyziologie MeSH
- kochlea patofyziologie chirurgie MeSH
- krysa rodu rattus MeSH
- nervový přenos * MeSH
- nervový útlum účinky léků fyziologie MeSH
- novorozená zvířata MeSH
- receptory GABA-A - agonisté farmakologie MeSH
- receptory GABA-A fyziologie MeSH
- receptory glycinu agonisté metabolismus fyziologie MeSH
- sluchové kmenové evokované potenciály fyziologie MeSH
- transportéry VIAAT metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The ability of pregnanolone glutamate (PA-Glu), pregnanolone hemisuccinate (PA-hSuc) and pregnanolone hemipimelate (PA-hPim), neuroactive steroids with a negative modulatory effect on excitatory N-methyl-d-aspartate receptors, to influence the functional activity of inhibitory γ-aminobutyric acid and glycine receptors was estimated. The GABA- and glycine-induced chloride currents (IGABA and IGly) were measured in isolated pyramidal neurons of the rat hippocampus using the patch-clamp technique. Compound PA-Glu was found to potentiate IGABA and to inhibit IGly, while PA-hSuc and PA-hPim inhibited both IGABA and IGly. Moreover, PA-Glu, PA-hSuc, and PA-hPim had a greater effect on desensitization than on the peak amplitude of IGly. At a high concentration of glycine (500 μM), the effect of neurosteroids on the peak amplitude of IGly disappeared, and the acceleration of desensitization remained. The conversion of PA-Glu into androstane glutamate (AND-Glu), an analogue that lacks the C-17 acetyl moiety, completely eliminated the effects on these receptors. Our results indicate that the C-17 acetyl moiety is crucial for the action on IGABA and IGly. Our results indicate that the pregnanolone derivatives, in contrast to the androstane analogues, modulate IGABA and IGly at low micromolar concentrations and this family of neurosteroids can be useful for future structure-activity relationship studies of the steroid modulation of other receptor types.
- MeSH
- hipokampus účinky léků fyziologie MeSH
- krysa rodu rattus MeSH
- neurony účinky léků fyziologie MeSH
- neurotransmiterové látky chemie farmakologie MeSH
- orgánové kultury - kultivační techniky MeSH
- potkani Wistar MeSH
- pregnanolon chemie farmakologie MeSH
- pyramidové buňky MeSH
- receptory GABA-A fyziologie MeSH
- receptory glycinu fyziologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Většinou různými podjednotkami tvořené a ligandem řízené iontové kanály, spolu se svými přídatnými bílkovinami a mnohočetnými bílkovinami, které se podílejí na jejich pohybu a receptorové odpovědi, jsou výzvou současného výzkumu. Cílem je charakterizovat a přesně definovat jejich funkční význam v normálním mozku, za patologicky změněných podmínek a v konečném důsledku objevit i nové skupiny léků. Pro jednotu myšlení a slovní formulace závěrů je třeba i jednotné terminologie, která především v případě ionotropních glutamátových receptoru byla značně nesourodá. V současnosti víme, že vzhledem k ukončené charakteristice lidského genomu se počet ligandem řízených iontových kanálů již nezvýší, což dává záruky, že názvosloví nově přijaté pro tuto velkou skupinu receptoru dále zpřesní naše formulační rozvahy v oblasti pokračujícího neuroťyziologického a neurofarmakologického výzkumu u savců. Kam se výzkum v současnosti ubírá, to napověděla 18. Neurofarmakologická konference ve Washingtonu (12.-14. 11. 2008).
The heteromeric nature of most ligand-gated ion channels, together with their accessory proteins and proteins involved in their trafficking and receptor-mediated responses pose multiple challenges to the present research. The receptor research must be well characterized for definition of their functional roles in normal brain and in disease states as well as for a new drug discovery. A consistent and systematic nomenclature for the individual subunits that comprise these receptors is highly desirable because of surprising disunity namely among ionotropic glutamate receptors. Now that we know that there are virtually no more ligand-gated ion channels to be discovered in the human genome, we hope that the proposed nomenclature will be used for neurophysiological and neuropharmacological research in mammalian species for a very long time. New functions for ligand-gated ion channels were presented during the 18th Neuropharmacology Conference (Washington, November 12-14, 2008).
- MeSH
- gating iontového kanálu fyziologie MeSH
- ligandy MeSH
- nikotinové receptory fyziologie klasifikace MeSH
- receptory buněčného povrchu fyziologie chemie klasifikace MeSH
- receptory GABA fyziologie klasifikace MeSH
- receptory glycinu fyziologie klasifikace MeSH
- sekvence aminokyselin fyziologie MeSH
- Publikační typ
- přehledy MeSH
