DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Endothelial cell
65
Calmodulin
ANP
Ca 2+ Ca 2+ Ca 2+ /Calmodulin
L-arginine
NOS
CHAPTER 3
GC
domains
Cellular
Effects
GTP
PKG
Cylic GMP
PDEs
GTP
α
β
Soluble GC
NO
NO
Cellular
Effects
Citrulline
Figure 3–11. Cyclic GMP signaling pathways. Formation of cyclic GMP is regulated by cell surface receptors with intrinsic guanlyate
cyclase activity and by soluble forms of guanylate cyclase (GC). The cell surface receptors respond to natriuretic peptides such as atrial
natriuretic peptide (ANP) with an increase in cyclic GMP. Soluble guanylate cyclase responds to nitric oxide (NO) generated from L-arginine
by nitric oxide synthase (NOS). Cellular effects of cyclic GMP are carried out by PKG and cyclic GMP-regulated phosphodiesterases
(PDEs). In this diagram, NO is produced by a Ca 2+ /calmodulin-dependent NOS in an adjacent endothelial cell. Detailed
descriptions of these signaling pathways are given throughout the text in relation to the therapeutic actions of drugs affecting these
pathways.
PHARMACODYNAMICS: MOLECULAR MECHANISMS OF DRUG ACTION
• Inhibiting IP 3
-mediated Ca 2+ release from intracellular stores.
• Phosphorylating voltage-gated Ca 2+ channels to inhibit Ca 2+
influx.
• Phosphorylating phospholamban, a modulator of the sarcoplasmic
Ca 2+ pump, leading to a more rapid reuptake of Ca 2+ into
intracellular stores.
• Phosphorylating and opening the Ca 2+ -activated K + channel leading
to hyperpolarization of the cell membrane, which closes
L-type Ca 2+ channels and reduces the flux of Ca 2+ into the cell
(Tsai and Kass, 2009).
NUCLEAR HORMONE RECEPTORS AND
TRANSCRIPTION FACTORS
In humans, nuclear hormone receptors comprise a
superfamily of 48 receptors that respond to a diverse
set of ligands. The receptor proteins are transcription
factors able to regulate the expression of genes controlling
numerous physiological processes such as reproduction,
development, and metabolism. Well-known
members of the family include receptors for circulating
steroid hormones such as androgens, estrogens, glucocorticoids,
thyroid hormone, and vitamin D. Other
members of the family are receptors for a diverse group
of fatty acids, bile acids, lipids, and lipid metabolites.
The latter receptors function as sensors for the metabolic
state of the cell and respond to changes in locally
available molecules (McEwan, 2009). Examples
include a number of nuclear receptors that are important
in inducing drug metabolizing enzymes, such as
the retinoic acid receptor (RXR); the liver X receptor
(LXR—the ligand is 22-OH cholesterol); the farnesoid
X receptor (FXR—the ligand is chenodeoxycholic acid);
and the peroxisome proliferator-activated receptors
(PPARs α, β, and γ ; 15 deoxy prostaglandin J2 is one
possible ligand for PPARγ; the cholesterol-lowering
fibrates bind to and regulate PPARγ). In the inactive
state, receptors for steroids such as glucocorticoids
reside in the cytoplasm and translocate to the nucleus