D. Inhibitors of Cyclic AMP Phosphodiesterase
VIII. CONCLUDING REMARKS
Many polypeptide hormones and biogenic amines are known to con
trol the formation of cyclic AMP by activation of adenyl cyclase. On the other hand, catecholamines and prostaglandins increase cyclic AMP formation in some tissues and decrease hormone-stimulated cyclic AMP levels in others. Direct inhibition of adenyl cyclase by hormones has not been shown. With the exception of insulin, which lowers cyclic AMP levels by activating phosphodiesterase, none of the hormones alters cyclic AMP levels by regulation of cyclic AMP phosphodiesterase activity. Moreover, phosphodiesterase activity in all tissues is severalfold higher than adenyl cyclase activity. There is now sufficient evidence to indicate that adenyl cyclase in most tissues is associated with the membranes of mitochondria and sarcoplasmic reticulum as well as with plasma membranes. The large polypeptide hormones that have no access to the interior of the cell activate only adenyl cyclase bound to the plasma membrane of the cell, whereas hormones that do enter the cell may, in addition, acti
vate adenyl cyclase bound to the membranes of intracellular organelles.
9. E N Z Y M E S R E G U L A T I N G C O N C E N T R A T I O N OF cAMP 4 2 3
Adenyl cyclase activity is also regulated by various ions, among which Ca
2+
and M g 2+
are of physiological importance. The hormones that enter the cell may alter the ionic concentration, which in turn may also acti
vate or inhibit adenyl cyclase bound to sites other than the plasma membrane. The mechanism by which hormones activate adenyl cyclase is still not fully understood. Hormones and ions may act at different sites to activate adenyl cyclase, as under certain conditions when there is loss of hormonal response, stimulation by ions is retained. An attrac
tive hypothesis is that the enzyme is a dimer consisting of a regulatory and a catalytic unit. This hypothesis further envisages an additional step, the so-called transducer, between the binding of the hormone to the regulatory unit and the subsequent activation of adenyl cyclase.
The response to hormones is lost on solubilization or extraction of mem
branes with lipid solvents, and this can be restored by addition of specific phospholipids.
It seems possible that the hormone receptor and adenyl cyclase are components of a common functional unit and that phospholipids are essential to maintain the integrity of the receptor site of the enzyme complex. On the other hand, ions such as Ca
2+
and M g 2+
control adenyl cyclase activity by direct binding to the catalytic unit.
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