PROPOFOL MODULATES ACTIVATION AND DESENSITIZATION OF GABA(A) RECEPTORS IN CULTURED MURINE HIPPOCAMPAL-NEURONS

Propofol (2,6 di-isopropylphenol) is an alkyphenol recently introduced for use as a general anesthetic. The modulation of GABA(A) receptor a ctivation and desensitization by propofol was studied using a rapid pe rfusion system and whole-cell voltage-clamp recordings from mouse hipp ocampal neurons. The effects of concentrations of propofol used clinic ally on single-channel and synaptic currents were also examined. Propo fol evoked current responses (EC(50) = 61 mu M) and shifted the dose-r esponse curve of GABA-activated current to the left without altering t he maximum of the GABA response. Preincubation with propofol and GABA led to desensitization of the GABA response (EC(50) = 454 mu M and 23 mu M, respectively). Saturating concentrations of GABA (600 mu M) evok ed currents that peaked and then declined in a biexponential fashion w ith fast and slow time constants of tau(f) = 1.0 sec and tau(s) = 3.5 sec. Propofol (10 mu M) did not change the amplitude of the peak respo nse but decreased the rates of decay approximately 1.5-fold and enhanc ed the steady-state current proportionately. Recovery from desensitiza tion was also biexponential (tau(f) = 11 sec, tau(s) = 69 sec) but not influenced by propofol. Single-channel recordings from outside-out pa tches demonstrated that both propofol and GABA activated channels with a 30 pS and 21 pS open state. Propofol increased the frequency but no t the duration or conductance of GABA-activated events. Miniature inhi bitory postsynaptic currents (mIPSCs) were evoked by the application o f hypertonic sucrose to the cell soma. Propofol (2 mu M) prolonged the decay time of mIPSCs to an extent similar to which it increased the o pen probability of GABA-activated channels (2.3- vs 3-fold). A sequent ial model, based on a previous scheme of GABA receptor gating (Weiss a nd Magelby, 1989), is presented to summarize propofol's actions on GAB A(A) receptor function. We show through simulation that the model reli ably reproduced the whole-cell tracings. Our results indicate that pro pofol's neurodepressive actions will be associated with enhancement of inhibitory synaptic transmission.