Regulation of GABAA receptor channels by anticonvulsant and convulsant drugs and by phosphorylation.
ABSTRACT The GABAA receptor channel is a highly regulated receptor. The function of the receptor may be modified by drugs which alter the rates of binding of GABA, modify the gating of the channel or block the channel. It is also likely that phosphorylation of the receptor subunits modifies the biophysical properties, stability or assembly of the receptor. While GABAergic inhibition plays a major role in the regulation of neuronal excitability, a role for altered GABAergic inhibition in the pathogenesis of epilepsy remains to be proven. The demonstration that GABAA receptors are composed of multiple subunits and that the properties and pharmacology of GABAA receptors are different for different subunit combinations suggests that GABAA receptor heterogeneity may be of importance in determining the properties of GABAergic inhibition in different regions of the nervous system. While it is clear that GABAA receptor heterogeneity is present in the nervous system, a role for receptor heterogeneity in the pathogenesis of epilepsy remains uncertain. GABAA receptor heterogeneity may have implications for the treatment of epilepsy. It is quite possible that drugs which regulate GABAergic function may have variable efficacy in different regions of the nervous system due to expression of receptors with subunits that have different sensitivity to allosteric regulators. Furthermore, it is likely that there are developmental changes in the stoichiometry or subunit composition of GABAA receptors rendering the developing nervous system more or less sensitive to the effects of GABAergic anticonvulsant drugs. In addition to the heterogeneous expression of GABAA receptors, other issues concerning the regulation of GABAergic function are of potential importance. The regulatory events that control the expression of specific receptor subtypes and levels of GABA receptors are unknown. The post-translational events that regulate GABAA receptor function are uncertain. It is possible that post-translational regulation of GABAA receptors by phosphorylation may contribute to altered GABAA receptor function in epilepsy. To understand the role of GABAA receptor heterogeneity in the pathogenesis of epilepsy will require the combination of biophysical and molecular biological techniques. It will be important to determine not only whether the properties of GABAA receptors have been altered in a specific form of epilepsy, but also whether gene expression has been altered.
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Article: Regulation of GABAA receptor channels by anticonvulsant and convulsant drugs and by phosphorylation.
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ABSTRACT: The absence epilepsy typical electroencephalographic pattern of sharp spikes and slow waves (SWDs) is considered to be due to an interaction of an initiation site in the cortex and a resonant circuit in the thalamus. The hyperpolarization-activated cyclic nucleotide-gated cationic I h pacemaker channels (HCN) play an important role in the enhanced cortical excitability. The role of thalamic HCN in SWD occurrence is less clear. Absence epilepsy in the WAG/Rij strain is accompanied by deficiency of the activity of dopaminergic system, which weakens the formation of an emotional positive state, causes depression-like symptoms, and counteracts learning and memory processes. It also enhances GABAA receptor activity in the striatum, globus pallidus, and reticular thalamic nucleus, causing a rise of SWD activity in the cortico-thalamo-cortical networks. One of the reasons for the occurrence of absences is that several genes coding of GABAA receptors are mutated. The question arises: what the role of DA receptors is. Two mechanisms that cause an infringement of the function of DA receptors in this genetic absence epilepsy model are proposed.01/2013; 2013:875834. DOI:10.1155/2013/875834
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ABSTRACT: Aminophylline is a complex of theophylline-ethylenediamine, where theophylline is the main component. Theophylline is a methyxanthine and besides inhibiting phosphodiesterase enzymes, it is also a nonselective adenosine antagonist. Several reports suggested the involvement of the brain adenosinergic system in the ethanol-induced motor incoordination. Thus, the objective of this work was to study the effects of the interaction of ethanol with aminophylline as assessed by behavioral tests in mice. Eight groups of male Swiss mice were used. The animals were treated with either distilled water (control) or ethanol (E; 2, 4, and 6 g/kg, orally) for 5 days, or with distilled water for 4 days, and on the fifth day with aminophylline (A; 5 and 10 mg/kg, intraperitoneally). In the association groups (association protocols), the animals were treated with ethanol (E; 6 g/kg, orally) for 4 days, and on the fifth day received aminophylline (A; 10 mg/kg, intraperitoneally), 30 min after the last ethanol administration (first protocol, E/A). In the second association protocol (A/E), ethanol was administered for 4 days, and on the fifth day the animals received aminophylline (A; 10 mg/kg, intraperitoneally), followed again by ethanol (E; 6 g/kg, orally) administration, 30 min later. E (6 g/kg) evoked a central nervous system depressor effect, by decreasing both the locomotor activity and rearing in the open field test, and A (5 and 10 mg/kg) showed opposite effects. However, the E/A or A/E associations blocked the ethanol effect. In the rota rod test, ethanol presented a muscular relaxant effect, which was decreased in both association protocols. In the tail suspension test, while the E/A association decreased immobility, A/E association increased it, as compared with controls. In conclusion, the effects of ethanol were inhibited by its association with aminophylline, suggesting that ethanol acts on the adenosine neurotransmission.Behavioural pharmacology 08/2009; 20(4):297-302. DOI:10.1097/01.FBP.0000358355.88022.fa · 2.19 Impact Factor
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ABSTRACT: Despite huge improvements in neurobiological approaches for investigating the functional properties of neurotransmitter receptors and ion channels, many difficulties are still encountered when focusing on the human brain. Electrophysiological studies aimed at performing direct determinations on human nervous tissue are limited by neurosurgery and also by pathophysiological conditions prevailing before and after the resective operation. The electrophysiological study of receptors and channels becomes difficult also in animal models when the cells are not accessible and/or the experiments last many hours, during which the examined nervous tissue usually becomes unhealthy. To increase the possibility of doing optimal electrophysiological recordings, addressed to investigate the functional properties of receptors and channels, more than two decades ago, foreign mRNAs were injected into Xenopus oocytes to heterologously express the receptors; and about a decade ago cell membranes were injected into the oocytes to directly transplant the native receptors. While the first approach needs complex procedures for mRNA isolation, the membrane preparations are simpler to obtain and the embedded receptors are transplanted in their own membrane, with their own glycosylation and together with any ancillary proteins they may have. Using injections of membranes isolated from fresh nervous tissues several issues have already been addressed and many questions can be answered in the near future. Strikingly, with this approach it has been possible to "resuscitate" receptors and ion channels from tissues kept frozen for many years. This review focuses on recently obtained information and on some new lines of biological research using receptor microtransplantation into oocytes.Progress in Neurobiology 06/2009; 88(1):32-40. DOI:10.1016/j.pneurobio.2009.01.008 · 10.30 Impact Factor