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The Journal of Neuroscience, July 28, 2004, 24(30):6667-6675; doi:10.1523/JNEUROSCI.1399-04.2004

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Cellular/Molecular
Slow Actions of Neuroactive Steroids at GABA_A Receptors

Hong-Jin Shu,¹ Lawrence N. Eisenman,² Deepani Jinadasa,¹ Douglas F. Covey,³ Charles F. Zorumski,^1,4 and Steven Mennerick^1,4

Departments of ¹Psychiatry, ²Neurology, ³Molecular Biology and Pharmacology, and ⁴Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110

Neuroactive steroids are potent and efficacious modulators of GABA_A receptor activity and are potent sedatives and anesthetics. These positive modulators of GABA_A receptors both potentiate the actions of GABA at the receptor and, at higher concentrations, directly gate the channel. The contribution of direct gating to the cellular and behavioral effects of neuroactive steroids is considered of little significance because it has been generally found that concentrations well above those needed for anesthesia are required to gate channels. By studying solitary glutamatergic neurons devoid of synaptic GABA input, we show that direct gating occurs and significantly alters membrane excitability at concentrations 100 nM. We propose that the relevance of direct gating has been overlooked partly because of the extremely slow kinetics of receptor activation and deactivation. We show that slow deactivation of directly gated currents does not result from an inherently tight ligand-receptor interaction because the slow deactivation is markedly accelerated by -cyclodextrin application. We hypothesize that steroids access the relevant GABA_A receptor site from a non-aqueous reservoir, likely the plasma membrane, and that it is slow reservoir accumulation and departure that accounts for the slow kinetics of receptor gating by neuroactive steroids.

Key words: allopregnanolone; GABA; neurosteroid; anesthesia; inhibition; hippocampus

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Received April 14, 2004; revised June 8, 2004; accepted June 9, 2004.

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