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.
