as studies of the innate function of receptor sites in the brain that bind delta-9 THC (tetrahydrocannabinol), the major psychoactive ingredient in marijuana.

FOCUSING IN ON RECEPTOR SITES

The close study of receptor sites is a lively subfield in itself. Previously unknown techniques of imaging and magnification can go beyond displaying the location of sites in the brain as a whole, down to the molecule-by-molecule layout of a single receptor. And the structures disclosed with these techniques are fascinating. No longer regarded as the passive “lock” of a “lock-and-key” mechanism, the receptors appear to work from a few simple elements and to achieve a wide range of effects.

Robert Lefkowitz and his colleagues at the Howard Hughes Medical Institute at Duke University have been looking closely at epinephrine and norepinephrine receptor sites for several years—practically the lifetime of this field so far. The adrenergic (epinephrine-using) receptors make a good model for studying a more general class of receptors, those that work through the G-proteins and bring about the production of second messengers inside the cell. Adrenergic receptors are found in most mammalian tissues and appear to fall into four types, called alpha-1, alpha-2, beta-1, and beta-2. They are associated with the two second-messenger systems discussed earlier: cyclic AMP and DG–IP3. Specifically, the beta receptors apparently increase the rate of production of cyclic AMP, and the alpha-2 receptors decrease it.

This was roughly the extent of what was known until about 1986. Then Lefkowitz and others succeeded in reading the full genetic sequence of the beta-2 receptor, which allowed them to clone the gene—in effect, to create thousands of copies of the beta-2 receptor in their laboratory.

What they learned in the process was astonishing: a single receptor site spans the cell membrane, like a built-in tunnel, no fewer than seven times. The arrangement consists of seven recurring clusters of 20 to 25 amino acids, each crossing the membrane and all held together by loops of amino acids within the cell and just outside the membrane. This pattern appears to hold good for the other kinds of receptors as well. In



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