Neurosteroid modulation of native and recombinant GABAA receptors (original) (raw)
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Neurosteroids and GABAA receptor function
Trends in Pharmacological Sciences, 1995
In 1994, a potent and selective interaction of the steroidal anaesthetic alphaxalone with the GABA, receptor was demonstrated. Subsequent studies established that certain naturally occurring steroids were potent positive allosteric modulators of the GABA* receptor. Although peripheral endocrine glands are an important endogenous source, the brain can synthesize 'neurosteroids', and these have the potential to influence the activity of the GAB% receptor in the CNS. Systemic administration of steroids have clear behavioural effects. In this article, Jeremy lambert and colleagues review recent advances in this field and discuss the therapeutic potential of this novel, non-genomic effect of steroids and investigate whether they may influence behaviour under physiological, or pathophysiological, conditions. Dundee. Dundee, UK DO1 9% 0 1995,
Potentiation of GABA A receptors by neurosteroids: Mechanisms and sites
International Congress Series, 2005
Neurosteroids increase the strength of neuronal inhibition by enhancing the activity of GABA-A receptors. The response to lower concentrations of GABA is increased in the presence of these drugs. One question is the nature of the basis for the potentiation — is there a change in the affinity of the receptor for GABA or an increase in the efficacy of activation? The answer for these drugs is that the major change occurs in the efficacy of activation, with no change in channel opening but a decrease in rates for entering states with a closed channel. There are at least 2 sites of action, which can be distinguished by the activity of steroid analogues with different structures. There are at least 3 mechanisms of action. Mutations of GABAA receptor subunits indicate that at least one site for steroid action is likely to be at the extreme carboxyl end of the γ2 subunit. Analysis of data obtained at a low concentration of GABA suggests that the ability of steroids to potentiate the GABAA ...
Neurosteroid modulation of GABAA receptors
Progress in Neurobiology, 2003
Certain metabolites of progesterone and deoxycorticosterone are established as potent and selective positive allosteric modulators of the ␥-aminobutyric acid type A (GABA A ) receptor. Upon administration these steroids exhibit clear behavioural effects that include anxiolysis, sedation and analgesia, they are anticonvulsant and at high doses induce a state of general anaesthesia, a profile consistent with an action to enhance neuronal inhibition. Physiologically, peripherally synthesised pregnane steroids derived from endocrine glands such as the adrenals and ovaries function as hormones by crossing the blood brain barrier to influence neuronal signalling. However, the demonstration that certain neurons and glial cells within the central nervous system (CNS) can synthesize these steroids either de novo, or from peripherally derived progesterone, has led to the proposal that these steroids (neurosteroids) can additionally function in a paracrine manner, to locally influence GABAergic transmission. Steroid levels are known to change dynamically, for example in stress and during pregnancy. Given that GABA A receptors are ubiquitously expressed throughout the central nervous system, such changes in steroid levels would be predicted to cause a global enhancement of inhibitory neurotransmission throughout the brain, a scenario that would seem incompatible with a physiological role as a selective neuromodulator. Here, we will review emerging evidence that the GABA-modulatory actions of the pregnane steroids are highly selective, with their actions being brain region and indeed neuron dependent. Furthermore, the sensitivity of GABA A receptors is not static but can dynamically change. The molecular mechanisms underpinning this neuronal specificity will be discussed with particular emphasis being given to the role of GABA A receptor isoforms, protein phosphorylation and local steroid metabolism and synthesis.
Brain Research Reviews, 2001
Upon administration, certain pregnane steroids produce clear behavioural effects including, anxiolysis, sedation, analgesia, anaesthesia and are anti-convulsant. This behavioural profile is characteristic of compounds that act to enhance the actions of GABA acting at the GABA receptor. In agreement, numerous studies have now demonstrated these steroids to be potent, positive allosteric modulators of the A GABA receptor. The pregnane steroids are synthesized in the periphery by endocrine glands such as the adrenals and the ovaries, but are A also made by neurons and glial cells in the central nervous system itself. Hence, these compounds could play both an endocrine and a paracrine role to influence neuronal excitability by promoting inhibition. Here we review evidence that the pregnane steroids are highly selective and extremely potent GABA receptor modulators and that their effects at 'physiological' concentrations (low nanomolar) may A be influenced by the subunit composition of the GABA receptor. This feature may underlie recent findings demonstrating the effects of A the neurosteroids on inhibitory synaptic transmission to be brain region dependent, although recent reports suggest that phosphorylation mechanisms may additionally influence neurosteroid sensitivity of the GABA receptor. Numerous synthetic steroids have been A synthesized in an attempt to therapeutically exploit the behavioural effects of the pregnane steroids and progress with this approach will be discussed. However, the demonstration that the steroids may be made within the central nervous system offers the alternative strategy of targeting the enzymes that synthesize / metabolise the neurosteroids to exploit this novel endocrine / paracrine interaction.
Mechanisms of neurosteroid interactions with GABAA receptors
Pharmacology & Therapeutics, 2007
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.
Effect of synthetic steroids on GABAA receptor binding in rat brain
Neuroscience, 2015
Neuroactive steroids, like allopregnanolone (A) and pregnanolone (P), bind to specifics sites on the GABAA receptor complex and modulate receptor function. They are capable to inhibit or stimulate the binding of GABAA receptor-specific ligands, like t-butyl-bicyclophosphorothionate, flunitrazepam and muscimol. We have previously characterized a set of oxygen-bridged synthetic steroid (SS) analogs to A or P using synaptosomes. Considering that the subunit composition of the GABAA receptor throughout the central nervous system affects the magnitude of the modulation of the GABAA receptor by NAS, we evaluated the action of two selected SS, in brain sections containing the cerebral cortex (CC) and hippocampus (HC) using quantitative receptor autoradiography. Both SS affected the binding of the three ligands in a similar way to A and P, with some differences on certain CC layers according to the ligand used. One of the SS, the 3α-hydroxy-6,19-epoxypregn-4-ene-20-one (compound 5), behaved...
Auto-modulation of neuroactive steroids on GABAA receptors: A novel pharmacological effect
Neuropharmacology, 2007
GABA A receptor function is modulated by various important drugs including neuroactive steroids that act on allosteric modulatory sites and can directly activate GABA A receptor channels at high concentrations. We used whole cell patch-clamp recordings and rapid applications of the neuroactive steroid alphaxalone to investigate repetitive steroid effects. Alphaxalone potentiation of submaximal GABA-evoked currents was enhanced significantly by repetitive coapplications at all investigated recombinant isoforms (a1b3d, a1b3g2L, a6b3d, a6b3g2L) and at GABA A receptors of differentiated human NT2 neurons. A similar increase of current amplitudes was induced by repetitive applications of a high steroid concentration without GABA. We refer to these reversible effects as auto-modulation because repeated interactions of steroids enhanced their own pharmacological impact at the receptor sites in a time and concentration dependent manner without affecting GABA controls. Pronounced auto-modulatory actions were also measured using the neurosteroid 5a-THDOC in contrast to indiplon, THIP, and pentobarbital indicating a steroid specificity. Protein kinase A inhibition significantly reduced alphaxalone auto-modulation at a1b3g2L, a6b3g2L, and a6b3d subtypes while it enhanced potentiation at a1b3d isoforms suggesting a crucial influence of receptor subunit composition and phosphorylation for steroid actions. Especially at extrasynaptic GABA A receptor sites containing the d subunit steroid auto-modulation may have a critical role in enhancing potentiation of GABA-induced currents.
Neurosteroid Access to the GABAA Receptor
Journal of Neuroscience, 2005
GABA A receptors are a pivotal inhibitory influence in the nervous system, and modulators of the GABA A receptor are important anesthetics, sedatives, anticonvulsants, and anxiolytics. Current views of receptor modulation suggest that many exogenous drugs access and bind to an extracellular receptor domain. Using novel synthetic steroid analogs, we examined the access route for neuroactive steroids, potent GABA A receptor modulators also produced endogenously. Tight-seal recordings, in which direct aqueous drug access to receptor was prevented, demonstrated that steroids can reach the receptor either through plasma membrane lateral diffusion or through intracellular routes. A fluorescent neuroactive steroid accumulated intracellularly, but recordings from excised patches indicated that the intracellular reservoir is not necessary for receptor modulation, although it can apparently equilibrate with the plasma membrane within seconds. A membrane impermeant neuroactive steroid modulated receptor activity only when applied to the inner membrane leaflet, demonstrating that the steroid does not access an extracellular modulatory site. Thus, neuroactive steroids do not require direct aqueous access to the receptor, and membrane accumulation is required for receptor modulation.