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 Previous Article
Journal of Neuroscience, Vol 14, 7747-7760, Copyright © 1994 by Society for Neuroscience
Propofol modulates activation and desensitization of GABAA receptors in cultured murine hippocampal neurons
BA Orser, LY Wang, PS Pennefather and JF MacDonald
Department of Anaesthesia, Sunnybrook Health Science Centre, Toronto, Ontario, Canada.
Propofol (2,6 di-isopropylphenol) is an alkyphenol recently introduced for
use as a general anesthetic. The modulation of GABAA receptor activation
and desensitization by propofol was studied using a rapid perfusion system
and whole-cell voltage-clamp recordings from mouse hippocampal neurons. The
effects of concentrations of propofol used clinically on single-channel and
synaptic currents were also examined. Propofol evoked current responses
(EC50 = 61 microM) and shifted the dose-response curve of GABA-activated
current to the left without altering the maximum of the GABA response.
Preincubation with propofol and GABA led to desensitization of the GABA
response (EC50 = 454 microM and 23 microM, respectively). Saturating
concentrations of GABA (600 microM) evoked currents that peaked and then
declined in a biexponential fashion with fast and slow time constants of
tau f = 1.0 sec and tau s = 3.5 sec. Propofol (10 microM) did not change
the amplitude of the peak response but decreased the rates of decay
approximately 1.5-fold and enhanced the steady-state current
proportionately. Recovery from desensitization was also biexponential (tau
f = 11 sec, tau s = 69 sec) but not influenced by propofol. Single- channel
recordings from outside-out patches demonstrated that both propofol and
GABA activated channels with a 30 pS and 21 pS open state. Propofol
increased the frequency but not the duration or conductance of
GABA-activated events. Miniature inhibitory postsynaptic currents (mlPSCs)
were evoked by the application of hypertonic sucrose to the cell soma.
Propofol (2 microM) prolonged the decay time of mlPSCs to an extent similar
to which it increased the open probability of GABA- activated channels
(2.3- vs 3-fold). A sequential model, based on a previous scheme of GABA
receptor gating (Weiss and Magelby, 1989), is presented to summarize
propofol's actions on GABAA receptor function. We show through simulation
that the model reliably reproduced the whole- cell tracings. Our results
indicate that propofol's neurodepressive actions will be associated with
enhancement of inhibitory synaptic transmission.
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