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Propofol Modulates Activation and Desensitization of GABA, Receptors in Cultured Murine Hippocampal Neurons

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Propofol Modulates Activation and Desensitization of GABA, Receptors in Cultured Murine Hippocampal Neurons The Journal of Neuroscience, December 1994, 74(12): 7747-7760 Propofol Modulates Activation and Desensitization of GABA, Receptors in Cultured Murine Hippocampal Neurons Beverley A. Orser,’ Lu-Yang Wang,* Peter S. Pennefather,‘,3 and John F. MacDonald2 ‘Department of Anaesthesia, Sunnybrook Health Science Centre, Toronto, Ontario, Canada, and *Departments of Physiology and Pharmacology, 3Faculty of Pharmacy and Faculty of Medicine, University of Toronto, Toronto, Ontario, M5S lA8 Canada Propofol (2,6 di-isopropylphenol) is an alkyphenol recently GABA, the major inhibitory neurotransmitter in the mam- introduced for use as a general anesthetic. The modulation malian brain, activates at least two distinct types of receptors of GABA, receptor activation and desensitization by pro- (for review, seeSivilotte and Nistri, 1991). The GABA, receptor pofol was studied using a rapid perfusion system and whole- is composedof several protein subunits that incorporate a Cll- cell voltage-clamp recordings from mouse hippocampal selective ion channel whereasGABA, receptors are singlesub- neurons. The effects of concentrations of propofol used clin- units that couple to G-proteins and thereby modulate K+ and ically on single-channel and synaptic currents were also ex- Ca*+ channels.The GABA, classof receptors mediate fast neu- amined. Propofol evoked current responses (EC,, = 61 @I) rotransmission in the majority of inhibitory synapses. and shifted the dose-response curve of GABA-activated The GABA, receptor is thought to be the site of action for a current to the left without altering the maximum of the GABA variety of drugs with hypnotic, anesthetic, and anticonvulsant response. Preincubation with propofol and GABA led to de- properties (Sieghart, 1992). Propofol, sedative benzodiazepines, sensitization of the GABA response (EC,, = 454 NM and 23 barbiturates, alphaxalone, and several neuroactive steroidsbind @I, respectively). Saturating concentrations of GABA (600 to distinct sites on GABA receptors and enhance GABA-acti- PM) evoked currents that peaked and then declined in a vated Cl- flux (Barker et al., 1987; Vicini et al., 1987; Collins, biexponential fashion with fast and slow time constants of 1988; Macdonald et al., 1989; Robertson, 1989; Concas et al., 7, = 1 .O set and 7, = 3.5 sec. Propofol(l0 PM) did not change 1991; Hales and Lambert, 1992; Hara et al., 1993). The mech- the amplitude of the peak response but decreased the rates anisms by which these drugs influence GABA, channel acti- of decay approximately 1.5fold and enhanced the steady- vation are not well understood. Anesthetics may alter agonist state current proportionately. Recovery from desensitization binding, receptor-channelcoupling or directly modulate channel was also biexponential (7, = 11 set, T, = 69 set) but not gating, and different concentrations of a drug may influence influenced by propofol. Single-channel recordings from out- receptor/channel behavior differently. For example, the ben- side-out patches demonstrated that both propofol and GABA zodiazepine flunitrazepam enhances GABA binding and in- activated channels with a 30 pS and 21 pS open state. Pro- creasesthe frequency of GABA-activated channel opening. pofol increased the frequency but not the duration or con- Flunitrazepam does not, however, directly activate the channel ductance of GABA-activated events. Miniature inhibitory or alter the mean duration of open events (Vinici et al., 1987). postsynaptic currents (mlPSCs) were evoked by the appli- In contrast, pentobarbitone, alphaxalone, and someneuroactive cation of hypertonic sucrose to the cell soma. Propofol (2 steroids activate channel opening in the absenceof exogenous PM) prolonged the decay time of mlPSCs to an extent similar GABA and increasethe mean open time of the channel (Barker to which it increased the open probability of GABA-activated et al., 1987; Macdonald et al., 1989; Mienville and Vicini, 1989; channels (2.3- vs 3-fold). A sequential model, based on a Twyman and Macdonald, 1992). Similarly, propofol alone in- previous scheme of GABA receptor gating (Weiss and Ma- creasesCll conductance and increasesthe open probability of gelby, 1969), is presented to summarize propofol’s actions GABA-activated channels (Hales and Lambert, 1992). It has on GABA, receptor function. We show through simulation not previously been determined if propofol increasesthe fre- that the model reliably reproduced the whole-cell tracings. quency or the duration of open’events. Our results indicate that propofol’s neurodepressive actions The efficacy of GABA-induced currents is also influenced by will be associated with enhancement of inhibitory synaptic receptor desensitization (Frosch et al., 1992; Oh and Dichter, transmission. 1992). GABA, receptor desensitization is influenced by a va- [Key words: propofol, 2,s di-isopropylphenol, GABA, de- riety of factors including agonist concentration, membrane po- sensitization, patch clamp, anesthetics] tential, the developmental stageof the cell, and drugs (Mierlak and Farb, 1988; Wiess, 1988; Frosch et al., 1992; Oh and Di- Received Apr. 1, 1994; revised June 6, 1994; accepted June 8, 1994. chter, 1992). Ligands other than GABA can also “cross-desen- This work was supported by a grant to J.F.M. and the Medical Research Council sitize” the receptor. Recently it was reported that preincubation of Canada Group “ Nerve Cells and Synapses.” B.A.O. is a fellow of the Medical Research Council ofcanada. We thank Ms. C. Bartlett and L. Brandes for technical with GABA reduced the responseto a subsequentapplication assistance. of propofol (Hara et al., 1993). It is therefore likely that propofol Correspondence should be addressed to Dr. B. Orser, Department of Physiology, University of Toronto, 1 King’s College Circle, Toronto, Ontario, Canada M5S can “cross-desensitize” GABA-mediated responses.The con- 1A8. centration dependenceof propofol-induced desensitization of Copyright 0 1994 Society for Neuroscience 0270-6474/94/147747-14$05.00/O GABA, receptors is of clinical interest as it has been suggested 7748 Orser et al. l Propofol Modulates GABA, Receptors that neuroexcitation observed during propofol anesthesia may pertonic sucrose solution (extracellular solution plus 0.25 M sucrose) to result from GABA, receptor desensitization and disinhibition the cell soma (see Bekkers and Stevens, 1989). Experiments were per- formed in the presence of Mg*+ (2 mM) to reduce the spontaneous release (Hara et al., 1993; Ries et al., 1994). of transmitters and to inhibit NMDA receptors. In addition, CNQX The purpose of this study was to investigate the effects of a (10 PM) was added to inhibit non-NMDA receptor-mediated excitatory wide range of concentrations of propofol (l-10,000 PM) on GA- synaptic currents. The amplitudes of the mIPSCs were constant over BA, receptor activation and desensitization by examining whole- the experimental period and currents were abolished following the ad- dition of bicuculline methiodide (10 PM) to the bath. Synaptic currents cell currents recorded from mouse hippocampal neurons. We were detected, averaged and fitted using an event detection program also examined the effects of low, clinically effective concentra- (SCAN, Strathclyde software program). For detection, a trigger level was tions of propofol (0.5-Z PM) on single-channel events and syn- set at approximately three times higher than the baseline noise. The aptic currents. We report that propofol influenced GABA, re- decay phase of the mIPSCs was fitted using a biexponential equation in the form Z(t) = A,exp(-t/T,) + A, exp(-t/T,) + c, where Z(t) is the ceptor function in three ways: low concentrations (Z-100 PM) current amplitude at any given time t, c is the baseline current, ~/and potentiated GABA-activated currents, increased the frequency 7, are the fast and slowtime constantsof current decay, respectively, of opening of GABA channels, and reduced the rate of desen- and A, and A, are the estimated fast and slow intercepts of the com- sitization; intermediate concentrations (1 O-l 000 PM) of pro- ponents at time zero. pofol directly activated GABA, channels and induced receptor Single-channel recording technique. Single-channel recording elec- desensitization; the third action, apparent at high concentrations trodes (6-10 Mfi) were coated with Svlnard (Dow Coming, Corp.) and filled with a sol&on containing (mM) cholineC1, 140; Cati,, 1; MgCl,, (600-10,000 FM), was to inhibit receptor/channel function pre- 2; EGTA, 11; HEPES, 10; and TEA, 10; pH 7.38. Outside-out patches sumably by a noncompetitive blocking action. To summarize were obtained as previously described and voltage clamped (Hamill et these findings we present a sequential model of channel gating al., 1981). Patches were positioned into the outflow from one of the by GABA and propofol that incorporates the modulating and perfusion barrels and the composition of the extracellular solution changed by moving the patch electrode. The extracellular perfusate direct blocking effects of propofol on GABA, receptor function. contained (in mM) choline Cl, 140; CaCl,, 1; MgCl,, 2; HEPES, 10; Preliminary results have appeared in an abstract form (Orser glucose, 30; tetrodotoxin, 300 nM; with or without 2 PM GABA, 2 pM et al., 1993a,b). propofol, or 2 PM GABA plus 2 PM propofol. Signals were filtered at 2 kHz (-3 dB) with a low-pass 4-pole Bessel filter, digitized (37 kHz, 94.4 kilosamples/sec, 14 bits), and recorded onto a VHS tape for off-line Materials and Methods analysis with a PC
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