Realising the therapeutic potential of neuroactive steroid modulators of the GABAA receptor (original) (raw)
2019, Neurobiology of Stress
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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.
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.
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