Page 40 - Basic _ Clinical Pharmacology ( PDFDrive )

26 SECTION I Basic Principles

insulin act on quite distinct receptor-effector systems, the clinician • How do cellular mechanisms for amplifying external chemical
must sometimes administer insulin to oppose the hyperglycemic signals explain the phenomenon of spare receptors?
effects of a glucocorticoid hormone, whether the latter is elevated • Why do chemically similar drugs often exhibit extraordinary
by endogenous synthesis (eg, a tumor of the adrenal cortex) or as selectivity in their actions?
a result of glucocorticoid therapy. • Do these mechanisms provide targets for developing new drugs?
In general, use of a drug as a physiologic antagonist produces
effects that are less specific and less easy to control than are the effects Most transmembrane signaling is accomplished by a small
of a receptor-specific antagonist. Thus, for example, to treat brady- number of different molecular mechanisms. Each type of mecha-
cardia caused by increased release of acetylcholine from vagus nerve nism has been adapted, through the evolution of distinctive protein
endings, the physician could use isoproterenol, a β-adrenoceptor families, to transduce many different signals. These protein families
agonist that increases heart rate by mimicking sympathetic stimula- include receptors on the cell surface and within the cell, as well as
tion of the heart. However, use of this physiologic antagonist would enzymes and other components that generate, amplify, coordinate,
be less rational—and potentially more dangerous—than use of a and terminate postreceptor signaling by chemical second messen-
receptor-specific antagonist such as atropine (a competitive antago- gers in the cytoplasm. This section first discusses the mechanisms
nist of acetylcholine receptors that slow heart rate as the direct targets for carrying chemical information across the plasma membrane
of acetylcholine released from vagus nerve endings). and then outlines key features of cytoplasmic second messengers.
Five basic mechanisms of transmembrane signaling are well
SIGNALING MECHANISMS & DRUG understood (Figure 2–5). Each represents a different family of
ACTION receptor protein and 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
Until now we have considered receptor interactions and drug effects and acts on an intracellular receptor; (2) a transmembrane recep-
in terms of equations and concentration-effect curves. We must tor protein whose intracellular enzymatic activity is allosterically
also understand the molecular mechanisms by which a drug acts. regulated by a ligand that binds to a site on the protein’s extra-
We should also consider different structural families of receptor cellular domain; (3) a transmembrane receptor that binds and
protein, and this allows us to ask basic questions with important stimulates an intracellular protein tyrosine kinase; (4) a ligand-
clinical implications:
gated transmembrane ion channel that can be induced to open or
• Why do some drugs produce effects that persist for minutes, close by the binding of a ligand; or (5) a transmembrane receptor
hours, or even days after the drug is no longer present? protein that stimulates a GTP-binding signal transducer protein
• Why do responses to other drugs diminish rapidly with prolonged (G protein), which in turn modulates production of an intracel-
or repeated administration? lular second messenger.

1 2 3 4 5
Drug

Outside
cell
R
Membrane R R R E
G
Inside
cell
A B Y Y~P C D

R

FIGURE 2–5 Known transmembrane signaling mechanisms: 1: A lipid-soluble chemical signal crosses the plasma membrane and acts on
an intracellular receptor (which may be an enzyme or a regulator of gene transcription); 2: the signal binds to the extracellular domain of a
transmembrane protein, thereby activating an enzymatic activity of its cytoplasmic domain; 3: the signal binds to the extracellular domain of a
transmembrane receptor bound to a separate protein tyrosine kinase, which it activates; 4: the signal binds to and directly regulates the open-
ing of an ion channel; 5: the signal binds to a cell-surface receptor linked to an effector enzyme by a G protein. (A, C, substrates; B, D, products;
R, receptor; G, G protein; E, effector [enzyme or ion channel]; Y, tyrosine; P, phosphate.)