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[3H]-MUSCIMOL, a POTENT Y-AMINOBUTYRIC ACID RECEPTOR AGONIST, to MEMBRANES of the BOVINE RETINA NEVILLE N

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[3H]-MUSCIMOL, a POTENT Y-AMINOBUTYRIC ACID RECEPTOR AGONIST, to MEMBRANES of the BOVINE RETINA NEVILLE N Br. J. Pharmac. (1980), 71, 259-264 BINDING OF [3H]-MUSCIMOL, A POTENT y-AMINOBUTYRIC ACID RECEPTOR AGONIST, TO MEMBRANES OF THE BOVINE RETINA NEVILLE N. OSBORNE Nuffield Laboratory of Ophthalmology, The University of Oxford, Walton Street, Oxford OX2 6AW 1 The binding of [3H]-muscimol, a potent y-aminobutyric acid (GABA) receptor agonist, to crude membrane preparations of bovine retina was studied, using a filtration method to isolate membrane- bound ligand. 2 Specific binding was found to be saturable and occurred at two binding sites with affinity con- stants of 4.3 nm and 38.2 nM. 3 Binding was sodium-independent, enhanced by both freezing and Triton X-100 treatment but abolished with sodium laurylsulphate. 4 The binding sites demonstrated a high degree of pharmacological specificity, GABA being a potent displacer of [3H]-muscimol. 5 A higher degree of [3H]-muscimol binding was associated with subcellular fractions enriched with photoreceptor synaptosomes rather than with fractions enriched with conventional synaptosomes. Introduction There is substantial evidence that y-aminobutyric acid lysed, in order to determine the subcellular localiz- (GABA) is a synaptic neuro-transmitter substance in ation of retinal GABA receptors. the vertebrate retina (see Graham 1974 for review). It has been demonstrated that GABA is synthesized and stored in certain neurones in the retina and that the Methods intracellular level can be altered by light (Lam, 1972; very important criterion of whether a sub- Bovine eyes were collected from the abattoir (British 1978). A the stance is a transmitter is to show the existence of Beef Co., Witney, Oxfordshire) within 10min of physiologically relevant receptor sites. Using specific animal's death. The retinas were then placed in radioactive [3H]-GABA, Enna & Snyder (1976) and Krebs-phosphate medium (Dawson, Elliot, Elliott & Redburn, Kyles & Ferkany (1979) were able to dem- Jones, 1972) at 2°C, containing 0.1 mM ascorbate and onstrate the existence of GABA binding sites in the transported to the laboratory, where they were rinsed et retina. These binding sites are, however, thought to in cold Krebs-bicarbonate medium (Dawson, al. represent not only the postsynaptic receptors for 1972) and either weighed out in 1 g portions and kept GABA, but also uptake sites. in the deep freeze until further use or fractionated into More recently, the potent GABA receptor agonist, various components. muscimol, has become available as a radioligand and Frozen retinas were subsequently homogenized has been used by a number of workers to characterize (1 g/l00 ml) in cold 0.05 M Tris/HCI buffer pH 7.4, in the synaptic GABA receptor in the mammalian brain a Teflon grinder with a glass pestle rotating at 900 (Beaumont, Chilton, Yamamura & Enna, 1978; Snod- rev/min with 6 up and down strokes. After centrifug- grass, 1978; Williams & Risley 1979). Muscimol has a ing the homogenates at 25,000 g for 30 min, the super- higher affinity for the GABA receptor than GABA natant was discarded and the pellet resuspended in itself and apparently labels the receptor rather than the same volume of Tris/HCl as above and centri- the uptake sites (see Johnston, 1978; Williams & Ris- fuged a second time at 25,000 g for 30 min. The resul- ley, 1979). tant pellet was resuspended in 1/10th of the original In the present study, a rapid filtration assay has volume of ice-cold Tris/HCl buffer and immediately been used to characterize the binding of [3H]-musci- assayed. Usually, 200 p1 of the membrane preparation mol to membranes of the bovine retina. Subcellular was incubated in 0.05 M Tris/HCI buffer pH 7.4 with fractions of the retina were also prepared and ana- various concentrations (0.5 to 300 nM) of [3H]-musci- 0007-1188/80/130259-06 SO1.00 C) Macmillan Publishers Ltd 1980 B.J.P. 71 /1- 260 NEVILLE N. OSBORNE 1100 0 Ah 0 w 0 0 'a 1000 0 -30 E E -0. a 900 0. C C 800 0 0 0 -o 700 -3 .0 E 600 c, IE E 500 E 400 100 200 300 10 20 30 40 50 60 70 80 90 [3H]-muscimol (nM) Time (min) Figure 2 Specific binding of various concentrations of [3H]-muscimol to retinal membrane preparations for a Figure 1 Time course of specific [3H]-muscimol bind- period of 30 min at 4°C. Each point is the mean of at ing to membranes prepared from bovine retina. [3H]- least three experiments each carried out in triplicate; muscimol concentration was 5 nm, incubation tempera- vertical lines show s.d. ture was 4°C. Specific binding is defined as the differ- ence between total [3H] muscimol binding and non- specific binding (where l0-' M GABA was also grinder and fractionated as described by Redburn present). Points are mean values of four experiments; (1977). Two populations of synaptosomes, one highly each experiment was carried out in triplicate. Percent- enriched in photoreceptor nerve endings (P1) and the age error varies from 5 to 10%. other containing synaptosomes derived from the inner plexiform layer (P2), were produced, suspended in mol (New England Nuclear, specific activity 13.7 Ci/ 0.05 M Tris/HCl buffer, homogenized and assayed for mmol) in the absence (total binding) or presence (non- [3H]-muscimol binding. specific binding) of 10-4M GABA. The final volume IC50s for the various compounds examined were was 0.5 ml. After incubation at 4°C for 30 min, the determined by running 3 to 6 concentrations of each reaction was terminated by the addition of 5 ml of compound in triplicate. Protein determinations were ice-cold Tris-HCl buffer, the sample rapidly filtered carried out by the method of Lowry, Rosebrough, onto Whatman GF/B glass fibre filters and washed on Farr & Randall (1951). the filter with 2 x 5 ml aliquots of ice-cold 0.05 M Tris/HCl buffer. Filters were placed in 10 ml scintilla- tion fluid (water: Triton X-100: toluene, 1:2:4 by vol, Results plus 0.04% PPO and 0.01% POPOP) and counted at an efficiency ranging between 20 and 27%. Specific Binding of [3H]-muscimol to membranes prepared binding was determined as the difference in the ct/min from retina stored at - 200C was stable for up to 30 bound to filters in the absence and presence of GABA days. Binding was independent of sodium up to and represented approximately 85% of the total 150 mm, was increased by 50 + 8% (± s.d., n = 5) fol- counts. Thin layer chromatography on silica pre- lowing treatment with 0.05% Triton X-100 and des- coated plates (Merck), using an ethyl acetate:isopro- troyed by heating to 100°C or treatment with 0.05% panol: ammonium hydroxide (9:7:5: by vol) system SDS. Binding of [3H]-muscimol to fresh retina prep- indicated that about 95% of membrane-bound isotope arations, as opposed to frozen material, was dimnin- was unchanged [3H]-muscimol. ished by 30 + 10%(±s.d., n = 3). When analysing the influence of Triton X-100 and The association of [3H]-muscimol with its binding sodium laurylsulphate (SDS), membranes were in- site in bovine retinal membranes was rapid, as shown itially incubated with the substances in Tris/HCI for in Figure 1. Owing to the limitation of the filtration 15 min at room temperature. The membrane prep- techniques, it was not possible to examine binding arations were then recovered by centrifugation at accurately at intervals of less than 2.5 min, but even at 25,000 g for 30 min and resuspended in Tris/HCl con- these times binding had reached a level approximately taining [3H]-muscimol. The binding of the [3H]-mus- a half of the eventual maximum. Equilibrium was cimol was then analysed in the usual way. reached at about 30 min after the start of the incuba- Fresh retinas were also hand-homogenized in tion, so this time was routinely chosen for the incuba- 0.32 M sucrose (pH 7.1) with a glass-Teflon tissue tion in subsequent experiments. [3H]-MUSCIMOL BINDING TO RETINAL MEMBRANES 261 0.2r 0.1 F 0) K. = 4.3nM 0 W- t B,.. = 3.75pmol/g cn 0) -0.11 m 'A Slope = 0.95 -om 01 = 38.2nm -0.2 KD 0 F i - 12.1 pmol/g 0) 0. -0.3- 1 2 3 4 5 6 7 8 9 10 11 12 13 -0.41- [ 3H]-muscimol bound (pmol/g) Figure 3 Scatchard plot of [3H]-muscimol to bovine -0.51- retinal membranes. Membranes were incubated with various concentrations of [3H]-muscimol as described -0.6L in Methods. The data in the curve shown above were 0.1 o -o.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 from two separate experiments carried out in triplicate. log [3H]-muscimol (nM) Figure 4 Hill plots using the data for the high affinity As seen from Figure 2, the specific binding isotherm binding site (see Figure 3) of [3H]-muscimol to retinal for various concentrations of [3H]-muscimol to reti- membranes. The line of best fit was estimated by the nal membrane preparations for a period of 30 min is a method of least squares (r = 0.95). hyperbolic curve, which approaches saturation at [3H]-muscimol concentrations above 200 nm. (Table 2, Figure 5). 3-Aminopropane-sulphonate, Non-specific binding (which was linear with con- GABA, isoguvacine, 4,5,6,7-tetrahydroisoxazole(5,3- centration) was subtracted from the total binding to C)pyridine-3-d (THIP), guvacine and imidazoleacetic give the specific binding isotherm (Figure 2). Scat- acid have substantially lower IC50 values than bicu- chard analysis (see Bennett, 1978) of the binding data, culline, picrotoxin or f-alanine.
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