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DISCOVERING THE BRAIN
a comparison of any two receptors, 40 to 50 percent of the sequence is identical—a high degree of conservation and an indication of how effective this structure must be.
As well as elucidating the fine structure of the beta-2 receptor, the cloning work of Lefkowitz and others turned up at least five more adrenergic receptors, all different from one another (in ways that had been imperceptible before the techniques of molecular genetics) and each with its own functions in the cell. From the point of view of clinical applications, this was, and continues to be, an exciting time for drug research, because it becomes possible to distinguish more closely among receptors and to select medications with increasing specificity. In the future it may even be possible to develop drugs targeted to particular subtypes of receptors and reduce unwanted side effects to a bare minimum.
The arrangement of seven membrane-spanning domains occurs widely throughout nature, in numerous guises. Many hormones, as well as transmitters, have receptors of this type; proteins called the opsins, which are precursors for the visual pigments, also fall in this category; and even in species as distant from ourselves as the slime mold, cyclic AMP is regulated through such a receptor. Meanwhile, with what is already known, many researchers are tackling the question of just what it is about the receptor's structure that determines function.
For questions of this sort, one technique is particularly effective —with the added advantage (or disadvantage, depending on one's taste) of sounding like something from a science fiction script. This technique is the creation of chimeras, creatures or structures that are artificially assembled from diverse genetic origins. Chimeric receptors created with recombinant DNA are excellent tools for study, because they allow the investigator to alter the receptor's structure, one small piece at a time, and then to observe any associated change in functioning. For example, researchers explored the activity of a chimeric receptor made up mostly of the alpha-2 type, with a small portion of beta receptor inserted into it. The receptor bound the substances that would be expected for an alpha receptor, but then it stimulated second-messenger production, as would be expected of a beta receptor. Thus, like the original chimera in Greek mythology (part-lion, part-goat, part-serpent),