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This Article Full Text Full Text (PDF) All Versions of this Article: 564/2/421    most recent jphysiol.2004.077297v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Smith, S. S Articles by Gong, Q. H. Search for Related Content PubMed PubMed Citation Articles by Smith, S. S Articles by Gong, Q. H.

¹ Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203, USA

Withdrawal from the GABA-modulatory steroid 3-OH-5-pregnan-20-one (3,5-THP) following exposure of female rats to the parent compound progesterone (P) produces a syndrome characterized by behavioural excitability in association with up-regulation of the 4 subunit of the GABA_A receptor (GABAR) in the hippocampus. Similar changes are seen after 48 h exposure to its stereoisomer, 3,5ß-THP. Here, we further characterize the effects of P withdrawal on GABAR kinetics, using brief (1 ms) application of 5–10 mM GABA to outside-out patches from acutely isolated CA1 hippocampal pyramidal cells. Under control conditions, GABA-gated current deactivated biexponentially, with _fast = 12–19 ms (45–60% of the current), and _slow = 80–140 ms. P withdrawal resulted in marked acceleration of deactivation (_fast = 3–7 ms and _slow = 30–100 ms), as did 48 h exposure to 3,5ß-THP (_fast = 5–8 ms; _slow = 40–120 ms). When recombinant receptors were tested in HEK-293 cells, a similar acceleration in _fast was observed for 4ß2 and 4ß22 GABARs, compared to 1ß22 and 5ß22 receptors. In addition, _slow was also accelerated for 4ß2 receptors, which are increased following steroid withdrawal. As predicted by the Jones-Westbrook model, this change was accompanied by reduced receptor desensitization as well as an acceleration of the rate of recovery from rapid desensitization. A theoretical analysis of the data suggested that steroid treatment leads to receptors with a greater stability of the bound, activatable state. This was achieved by altering multiple parameters, including desensitization and gating rates, within the model. These results suggest that fluctuations in endogenous steroids result in altered GABAR kinetics which may regulate neuronal excitability.

(Received 12 October 2004; accepted after revision 7 February 2005; first published online 10 February 2005)
Corresponding author S. S. Smith: Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203, USA. Email: sheryl.smith{at}downstate.edu

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