Primary alcohols modulate the activation of the G protein-coupled receptor rhodopsin by a lipid-mediated mechanism.

The visual pigment rhodopsin is a prototypical member of the G protein-coupled receptor superfamily. In this study, we have investigated the effect of a series of n-alcohols on the formation of metarhodopsin II (MII), the photoactivated conformation of rhodopsin, which binds and activates transducin. When rhodopsin was photolyzed in the presence of several n-alcohols, increased MII formation was observed in the order ethanol > butanol > hexanol, whereas longer chain n-alcohols inhibited MII formation with decanol > octanol. The magnitude of the stimulatory effects was greater in a more highly unsaturated phospholipid. Alcohols, which enhanced MII formation also increased phospholipid acyl chain packing free volume, while those that decreased this bilayer property inhibited MII formation. An apparent discontinuity in the effect of these alcohols results when their potency is calculated in terms of the total aqueous alcohol concentration. In sharp contrast, a continuous variation in their behavior is observed, when their potency is calculated in terms of the amount of alcohol partitioned in the membrane. Our findings strongly support a lipid-mediated mechanism of action for alcohols on rhodopsin and, by analogy, for other G protein-coupled receptors.