Signaling Mechanisms & Drug Action

SIGNALING MECHANISMS & DRUG ACTION

Until now we have considered receptor interactions and drug effects in terms of equations and concentration-effect curves. We must also understand the molecular mechanisms by which a drug acts. Such understanding allows us to ask basic questions with important clinical implications:

Why do some drugs produce effects that persist for minutes, hours, or even days after the drug is no longer present?

·  Why do responses to other drugs diminish rapidly with pro-longed or repeated administration?

·  How do cellular mechanisms for amplifying external chemical signals explain the phenomenon of spare receptors?

·  Why do chemically similar drugs often exhibit extraordinary selectivity in their actions?

·           Do these mechanisms provide targets for developing new drugs?

Most transmembrane signaling is accomplished by a small number of different molecular mechanisms. Each type of mecha-nism has been adapted, through the evolution of distinctive pro-tein families, to transduce many different signals. These protein families include receptors on the cell surface and within the cell, as well as enzymes and other components that generate, amplify, coordinate, and terminate postreceptor signaling by chemical sec-ond messengers in the cytoplasm. This section first discusses the mechanisms for carrying chemical information across the plasma membrane and then outlines key features of cytoplasmic second messengers.Five basic mechanisms of transmembrane signaling are well understood (Figure 2–5). Each uses a different strategy to circumvent the barrier posed by the lipid bilayer of the plasma membrane. These strategies use (1) a lipid-soluble ligand that crosses the membrane and acts on an intracellular receptor; (2) a transmembrane receptor protein whose intracellular enzymatic activity is allosterically regulated by a ligand that binds to a site on the protein’s extracellular domain; (3) a transmembrane receptor that binds and stimulates a protein tyrosine kinase; (4) a ligand-gated transmembrane ion channel that can be induced to open or close by the binding of a ligand; or (5) a transmembrane receptor protein that stimulates a GTP-binding signal transducer protein (G protein), which in turn modulates production of an intracellu-lar second messenger.Although the five established mechanisms do not account for all the chemical signals conveyed across cell membranes, they do transduce many of the most important signals exploited in pharmacotherapy.