The adrenergic system is a crucial component of the sympathetic nervous system and has widespread effects throughout the body. “Adrenergic” comes from “Andren,” relating to “adrenaline” (a stress hormone also referred to as epinephrine in the U.S.), and “ergic” derived from the Latin “ergy,” meaning “at work.” Put together, the word “adrenergic” is the condensed form of “adrenaline at work.” The story of the discovery of the adrenergic receptors spans over a hundred years—and is still unfolding to this day.

Enter the history

The story starts with Henry Hallett Dale, otherwise known as H.H. Dale. Before we had any concept of how the adrenergic system communicated, Dale performed a novel experiment in 1906. Adrenaline typically causes blood vessels to decrease in circumference, called vasoconstriction. Dale treated blood vessels with the fungus ergot and watched it block the effects of adrenaline and prevent vasoconstriction. This led Dale to conclude that the effects of adrenaline on a blood vessel are mediated through a receptor. Receptors act a signal transducer and when activated by a molecule, cause a physiologic response. For example, if adrenaline is a key and the receptor is a lock, ergot acted like chewing gum jammed in the lock (receptor) to prevent the key from working (causing vasoconstriction). This discovery shook the scientific world at the time and established the concept of the adrenergic receptor. In 1932, to reflect his body of work, Dale was knighted and became Sir Dale. In 1936, he received the Nobel Prize in Physiology or Medicine.

Discovery of alpha and beta

As a testament to science’s slower pace, more than 40 years passed before another breakthrough came along. In 1948, American pharmacologist Raymond Ahlquist tested new compounds and discovered that some receptors showedinhibitory effects—they did the opposite of what adrenaline was thought to do.

Ahlquist then divided the receptors into two classifications: alpha-adrenergic to mean those that cause vasoconstriction and beta-adrenergic or for vessel widening or vasodilating. Beta receptors provided the foundation for the well-known drug class beta blockers. The publication of this finding was first rejected but was eventually published in the American Journal of Physiology.    

Beta-adrenergic receptors again and again

In 1967, Alonzo Lands and colleagues discovered that beta-adrenergic receptors have different effects on different organ systems. For example, in the heart they controlled rate and contractility, but in the blood vessels they could cause vasodilation. Because of these differences and ability to be distinctly targeted with different medicines, Lands and colleagues subdivided the beta-adrenergic receptors into beta-1, predominantly found in the heart and beta-2, primarily found in blood vessels.

The saga continues

Another couple of decades later, in 1989, a third receptor was found. Aptly named beta-3, it is widely expressed in fat cells and several other organs and can also be distinctly targeted with newer drugs.

Adrenergic receptors forever

Since the late 1980s, the larger story of the adrenergic receptors has largely tapered off, although we are still learning a lot about them. A fourth isoform has been proposed, but there hasn’t been enough data to support its official discovery. With the interval in major breakthroughs with the adrenergic receptors typically spanning a couple decades, we are due for one soon.