Increased membrane cholesterol reduces the potentiation of GABA(A) currents by neurosteroids in dissociated hippocampal neurones.
The effects of increased membrane cholesterol on the potentiation of GABA(A) currents by pregnanolone (5beta-pregnan-3alpha-ol-20-one), allopregnanolone (5alpha-pregnan-3alpha-ol-20-one), alphaxalone (5alpha-pregnan-3alpha-ol-11,20-dione) and propofol were investigated in acutely dissociated rat hippocampal neurones using the whole-cell patch clamp technique. Cholesterol enrichment of the neurones, isolated from 10 to 16-day-old Wistar rat brains, was achieved by incubation with cholesterol + phosphatidylcholine liposomes. Cholesterol enrichment (25.8+/-3.4%) reduced the potentiation of GABA(A) currents by pregnanolone (0.3 and 1 microM), allopregnanolone (1 microM) and alphaxalone (1 microM) but the potentiation of GABA(A) currents by propofol (5 microM) was not affected. Acute application of cholesterol (1 microM) did not significantly change the potentiation of GABA(A) currents by pregnanolone (1 microM). These results suggest that cholesterol within the neuronal membrane may compete with neurosteroids for their sites of action on the GABA(A) receptor or modulate the potentiating effect of the neurosteroids in some other ways.
Sooksawate
T
T
Department of Pharmacology, The School of Pharmacy, University of London, UK.
Simmonds
M A
MA
D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008081:Liposomes; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D011277:Pregnanediones / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013256:Steroids / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects; D013570:Synaptic Membranes / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D008081:Liposomes; D011277:Pregnanediones; D011963:Receptors, GABA-A; D013256:Steroids; D005680:gamma-Aminobutyric Acid; D002784:Cholesterol; C006477:alphaxalone; D011280:Pregnanolone; D015742:Propofol