Ever since Sutherland & Rail (1957) discovered that adenosine-Y,5'-monophosphate (c-AMP) mediates the epinephrine activation of liver glycogenolysis, the list of hormones which elevate the concentration of the nucleotide in their target tissues is increasing (Table 1, Robison, Butcher & Sutherland, 1967). The cyclic nucleotide or its dibulyryl derivative mimics several hormonal effects and this is one of the several lines of evidence which have implicated the nucleotide as a mediator. The cellular concentration of c-AMP is regulated by two enzymes, adenyl cyclase which cyclizes the y-phosphate group of adenosine triphosphate in the presence of Mg z+ (Sutherland, Rail & Menon, 1962) and diesterase which hydrolyses c-AMP to adenosine monophosphate. In most tissues the cyclase is bound to the plasma membrane upon which the enzyme activity appears to depend.
Several enzymes which exhibit allosteric interaction (Koshland & Neet, 1968) have regulatory sites separate from catalytic sites. Interaction of effector ligands at the regulatory site influences the activity at the catalytic site. Robison et al. (1967) have postulated that adenyl cyclase has distinct regulatory and catalytic sites and that the former is also the fl-adrenergic receptor. This model does not explain how the same regulatory or receptor site can recognize stereospecifically the peptide hormones and epinephrine and produce the same activation effect. Also the tissue specificity of peptide hormones and an almost general effect of epinephrine cannot be satisfactorily explained. Recently, Bitensky, Russel & Robertson (1968) have suggested two different adenyl cyclase enzymes in liver but their experimental evidence does not appear to be conclusive. A model which could explain the activation of adenyl cyclase by polypeptide hormones as well as by epinephrine is now proposed.
It is known that the secondary amino group together with the catechol group are essential for the activity of epinephrine (Marley, 1964). Epinephrine activates the adenyl cyclase of liver, brain, skeletal muscle, cardiac muscle, adipose tissue, lung, spleen, avian erythrocytes and ventral frog skin and probably of other tissues as well (Robison et al., 1967). These observations suggest that the stereochemistry (or the pattern of forces) of the regulatory site of adenyl cyclase is highly complementary to that of epinephrine and also this specificity is similar in most tissues.