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Intracellular Receptors: New Instruments for a Symphony of Signals In the late eighteenth century, it was proposed on theoretical grounds that each of the body's organs, beginning with the brain, must be a factory and laboratory of a specific humor which it returns to the blood , and that these circulating signals are indispensable for the life of the whole (Bordeu 1775). During the nineteenth cen- tury, some remarkable physiological experiments revealed the actions of humoral factors that affected the for and function of multiple tissues, organs and organ sys- tems within the body (Berthold 1849); much later, the chemical and molecular na- ture of some of those factors was determined. Against this deep historical backdrop of the founding studies of intercellular signaling, molecular biology sprang into existence a mere forty years ago, rooted in the revelation of regulable gene expression in bacteria. But contemporaneous with those classical analyses of transcriptional regulation of the lactose operon, the mod- em era of signal transduction was inaugurated by the identification of cAMP as a second messenger --- an intracellular mediator of hormonal activation of glycogen catabolism (Sutherland and RaIl 1960). Later in that same decade, it emerged that cAMP is a critical signal not only in metazoans, but even in bacteria, where it serves an analogous function as a critical switch that activates expression of genes re- quired for catabolism of complex carbon sources, including those of the lactose operon.

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