The overt physiological expression of the interaction between a ligand and its receptor on a cell surface is the product of two distinct steps-the formation of the ligand-receptor complex, and the transmission of the relevant message into the cell interior. The accessibility of surface receptors to ligand binding can be modulated by changes in the membrane lipid fluidity which, in turn, may mediate a shift in the equilibrium position of membrane proteins (1-4). Signal transduction, either through activation of adenylate cyclase by the ligand-receptor complex (5, 6) or by microaggregation of ligand-receptor complexes (7,8), is associated with lateral movements of components of the membrane which are determined, at least partially, by lipid fluidity (9). This net "passive" modulation of a receptor function by lipid fluidity is therefore a rapid physical process which does not require metabolic energy. It has been suggested (10) that this mechanism may play a key role in the modulation of receptor function in fast cellular processes such as neurotransmission.The accessibility of a receptor binding site, which is a prerequisite for its function, and the extent and direction of its displacement by changes in the lipid fluidity are determined primarily by the geometry of the receptor in the immediate lipid environment. The 3-adrenergic receptor, for example, is affected by lipid fluidity in a different manner in different cells. When lipid microviscosity is decreased, the receptor be- (Colnbrook, England). The following drugs were used: methysergide (Sandoz), metergoline (Farmitalia), cinanserin (Squibb), mianserin (Organon), methiothepin (Hoffmann-LaRoche), fluxethine (Eli Lilly), and haloperidol (Abic, Israel).Media for Lipid Modulation. A modification of a previous procedure (14) was used, in order to avoid using ethanol. CholSuc was dissolved in glacial acetic acid (40 mg/ml) by heating and stirring. The hot solution was diluted to 100 vol with 50 mM Tris-HCI, pH 7.4/3.5% PVP, with vigorous stirring. The pH was then readjusted to 7.4 with solid Tris base. The resulting translucent suspension of CholSuc in 170 mM Tris acetate buffer was then used for modulating membrane fluidity. Solutions of egg lecithin (80 mg/ml), stearic acid (6 mg/ml), and linoleic acid (6 mg/ml) in glacial acetic acid were used in a similar manner to form the corresponding media.Crude Membrane Preparation (Crude Homogenate). Male BALB mice (20-25 g; 6-8 weeks old) were decapitated, and their forebrains (whole brain minus cerebellum) were rapidly removed and homogenized in 20 vol of ice-cold 50 mM Tris-HCI (pH 7.4) buffer in an Ultra-Turrax homogenizer (setting 6, 20 sec). The homogenates were then centrifuged at 42,000 X g for 10 min at 4°C in a Sorvall RC-5B centrifuge. The pellets were resuspended in 10 vol of the same buffer (100 mg of tissue per ml) and incubated for 2 hr with varying volumes of the lipid suspensions described above. Between 1 and 30 ml of lipid Abbreviations: CholSuc, cholesteryl hemisuccinate; PVP, polyvinylpyrrolidone...
