The G lucagon-sensitive Adenyl Cyclase System in Plasma Membranes

Glucagon and fluoride ion stimulate the activity of a common adenyl cyclase system in p lasma membranes isolated from rat liver. Their actions are noncompeti t ive indicating that they act at separate sites in this system. Manganous ion, above 5.0 mM, inhibited selectively the response of the enzyme to glucagon. Inorganic pyrophosphate (1.5 mu), on the other hand, inhibited the response of the enzyme to fluoride but enhanced the response to glucagon. The inhibitory effect of pyrophosphate was noncompeti t ive with fluoride ion. Highly purified phosphol ipase A caused a selective loss of the g lucagon response and enhanced the stimulatory effect of fluoride ion. Treatment of liver membranes with digitonin also caused a selective loss of hormone response. Inactivation of g lucagon response by digitonin was not restricted to the liver membrane adenyl cyclase system; incubation of ghosts of fat cells with digitonin resulted in loss of response of the adenyl cyclase system to glucagon, adrenocorticotropin, secretin, and epinephr ine at very low concentrations of the detergent. Digitonin enhanced the response of the fat cell system to fluoride ion. Sodium dodecyl sulfate, over a narrow range of concentrat ions, inhibited the response of liver membrane adenyl cyclase to glucagon, and enhanced the enzyme’s response to fluoride ion. Other detergents caused a parallel loss of the response to both fluoride ion and glucagon. The present f indings suggest that g lucagon and fluoride ion activate adeny cyclase by different mechanisms. It is possible that these agents react through different molecular entities in this complex enzyme system.