Phenobarbital selectively modulates the glucagon-stimulated activity of adenylate cyclase by depressing the lipid phase separation occurring in the outer half of the bilayer of liver plasma membranes

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Abstract
The glucagon-stimulated (coupled) activity of rat liver plasma membrane adenylate cyclase could be selectively modulated by the anionic drug phenobarbital, whereas the fluoride-stimulated (uncoupled) activity remained unaffected. The cationic drug phenobarbital may preferentially interact with the external half of the bilayer, as the negatively charged phospholipids are found at the cytosol-facing side. This results in a selective fluidization of the external half of the bilayer, leading to a depression in the high-temperature onset of the lipid phase transition (from 28 to 16.degree. C) occurring there. This was detected both by ESR analysis, using a fatty acid spin probe, and by Arrhenius plots of glucagon-stimulated activity, where the enzyme forms a trans-membrane complex with the receptor and is sensitive to the lipid environment of both halves of the bilayer. In the absence of hormone, adenylate cyclase only senses the lipid environment of the inner (cytosol) half of the bilayer. Thus its fluoride-stimulated activity and Arrhenius plots of this activity remained unaffected by the presence of phenobarbital (less than 12 mM) in the assay. Independent modulation of the fluidity or chemical constituents of each half of the bilayer apparently can selectively affect the receptor-coupled and uncoupled activities of adenylate cycl4se.

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