Mechanisms and Sites of Action

The sites of action of both excitatory and inhibitory neuroactive steroids are depicted in Fig. 2. The inhibitory actions of the GABAergic neuroactive steroids are mediated by synaptic and extrasynaptic GABAA receptors. These steroids interact with GABAa receptors via specific binding sites on a subunits that allosterically modulate binding to GABA and benzodiazepine recognition sites (Hosie et al. 2006). GABAa receptor function is enhanced by potentiation of GABA-mediated CP conductance as well as direct stimulation of CP conductance in both ► voltage clamp studies and [36CP] flux studies. GABAA receptors appear to have multiple neurosteroid recognition sites that likely reflect distinct recognition sites on GABAA receptor subtypes. Neuroactive steroids modulate both synaptic and extrasynaptic GABAA receptors with lower potency at synaptic receptors that contain g2 subunits and higher potency at extrasynaptic receptors that contain 8 subunits (see Belelli and Lambert 2005, for review). These steroids also have modulatory actions at serotonin type-3 receptors neuronal ► nicotinic

Neuroactive Steroids. Fig. 2. Sites of action of inhibitory and excitatory neuroactive steroids. The inhibitory actions of GABAergic neuroactive steroids are mediated by synaptic and extrasynaptic g-aminobutyric acid type-A (GABAa) receptors. The excitatory actions of sulfated steroids such as pregnenolone or dehydroepiandrosterone (DHEA) sulfate are partially mediated by direct, but low potency, activation of NMDA receptors and inhibition of GABAa receptors. Pregnenolone sulfate also potently inhibits GABA or glutamate release at nerve terminals. These effects are mediated by presynaptic sigma-1 receptors. Neuroactive steroids have modulatory actions at serotonin type-3 receptors, neuronal nicotinic acetylcholine receptors and voltage-activated calcium channels, albeit with micromolar potency at these sites. Another site of action includes the nuclear pregnane-X receptor that regulates P450 enzymes and steroid hormone levels across many tissues.

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