Second Messengers

When faced with a predator in the wild, the potential prey has one of two options: fight or flight. To prepare for action, the body responds by increasing heart rate, breathing faster, activating voluntary muscles, and increasing blood glucose (sugar). These bodily responses to stress are mediated by releasing the hormone epinephrine (adrenaline) from the adrenal glands. The glucose obtained from carbohydrate sources can be immediately utilized for energy generation or stored in the liver and muscle as glycogen for later use. When epinephrine is released, it binds to a receptor protein on the surface of the liver or muscle, and this serves as a signal, setting into motion a series of biochemical reactions, culminating in glucose release. This is a three-stage process, the first involving hormonereceptor binding (reception), and concluding with glucose formation (response) in the third stage. But what occurred in the second stage was a mystery.

The American pharmacologist Earl Sutherland had studied these reactions during the 1940s and 1950s and knew that the enzyme glycogen phosphorylase was directly involved. But, when he added this enzyme and epinephrine to liver slices in a test tube, no glucose was formed. Sutherland sought to determine the nature of the missing second stage—transduction—and identify the linking chemical responsible for converting the signal hormone (or first messenger) on the liver cell surface into a response within the cell.

That linking chemical—the second messenger—was cyclic adenosine monophosphate or cAMP. In a series of 1956–1957 papers, Sutherland described the sequence of events: The epinephrinereceptor union activates the enzyme adenylyl cyclase located on the liver cell surface which, in turn, promotes the conversion of adenosine triphosphate (ATP) to cAMP. Through a series of subsequent enzyme-catalyzed reactions, glycogen phosphorylase is activated and glycogen is broken down to glucose. Sutherland was awarded the 1971 Nobel Prize for demonstrating the biological role of cAMP.

When confronted by an adversary, the choice is “fight or flight.” In either case, the body prepares itself by releasing epinephrine, which activates an increase in blood glucose. The second messenger (cAMP) provides the link between the activation of a receptor on the surface of a liver cell and the release of energy-providing glucose.

As a second messenger, cAMP plays a role in such diverse cellular activities as energy metabolism, division and differentiation, ion movement, and muscle contractions, and has been shown to be involved in signal transduction in animals, plants, fungi, and bacteria.