this receptor is a fabrication, a blend of incongruous parts. With continued fine-tuning of the size and precise placement of chimeric insertions, researchers should be able to isolate the specific amino acids in the receptor that determine one or another biological function.

The dynamic nature as well as the versatility of the adrenergic receptors offers appealing avenues for further investigation. For instance, what takes place at the molecular level during the process of desensitization, in which the response drops in intensity over time even though the stimulus remains constant? All the evidence thus far suggests that there may be a new—previously unknown—protein kinase involved in desensitization, which essentially works the “off” switch for a receptor that has bound to a first messenger. Lefkowitz and his coworkers named such a substance, sight unseen, BARK—for beta adrenergic receptor kinase—and then proceeded to find it. BARK cooperated by revealing itself as a distant relative of the second messenger-sensitive protein kinases.

BARK works in cooperation with another newly discovered protein, barrestin (for “beta-arrestin”), to inactivate the receptor site temporarily. The mechanism works in two steps. When BARK is called into action by the binding of a neurotransmitter, it adds a phosphate group to the receptor site, thereby changing its shape. Barrestin can now bind easily to the receptor site and complete the action of the “off” switch.

The proving of a hunch can be its own best reward—particularly for the scientist, who is often pursuing something as intangible as a closer look at some aspect of nature. But the discovery of BARK and barrestin brings a practical bonus. In the development of pharmaceutical aids to reduce desensitization and thereby prolong the therapeutic effect of some drugs, BARK and barrestin offer two targets that were completely unknown only a few years ago.


While the discovery of neurotransmitters and elucidation of the structure of their receptor sites have been proceeding apace, another family of receptor sites is also becoming increasingly well known to neuroscience. This family comprises

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