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

68 FADD/TRAF2, and caspase 8, which results in the activation of caspase
8. The FAS and TRAIL receptors recruit different adaptors,
termed FADD/MORT, which are capable of attracting and then activating
caspase 8 by autoproteoyltic cleavage. Regardless of the
upstream complexes that activate caspase 8, stimulation of its proteolytic
activity leads to the activation of caspase 3, which initiates the
apoptotic program. The final steps of apoptosis are carried out by
caspase 6 and 7, leading to degradation of enzymes, structural proteins,
and DNA fragmentation characteristic of cell death (Danial
and Korsmeyer, 2004; Wilson et al., 2009) (Figure 3–13).
The internal apoptosis pathway can be activated by signals
such as DNA damage leading to increased transcription of the p53
gene and involves damage to the mitochondria by pro-apoptotic
members of the Bcl-2 family of proteins. This family includes proapoptotic
members such as BAX, Bak, and Bad, which induce damage
at the mitochondrial membrane. There are also anti-apoptotic
Bcl-2 members, such as Bcl-2, Bcl-X, and Bcl-W, which serve to
inhibit mitochondrial damage and are negative regulators of the system
(Rong and Distelhorst, 2008). When DNA damage occurs, p53
transcription is activated and holds the cell at a cell cycle check point
until the damage is repaired. If the damage cannot be repaired, apoptosis
is initiated through the pro-apoptotic Bcl-2 members such as
BAX. BAX is activated, translocates to the mitochondria, overcomes
the anti-apoptotic proteins, and induces the release of cytochrome c
and a protein termed the “second mitochondria-derived activator of
caspase” (SMAC). SMAC binds to and inactivates the inhibitors of
apoptosis proteins (IAPs) that normally prevent caspase activation.
Cytochrome C combines in the cytosol with another protein, apoptotic
activating protease factor -1 (Apaf-1), and with caspase 9. This
complex leads to activation of caspase 9 and ultimately to the activation
of caspase 3 (Ghobrial et al., 2005; Wilson et al., 2009). Once
activated, caspase 3 activates the same downstream pathways as the
external pathway described above, leading to the cleavage of proteins,
cytoskeletal elements, DNA repair proteins, with subsequent
DNA condensation and membrane blebbing that eventually lead to
cell death and engulfment by macrophages (Figure 3–13)
SECTION I
GENERAL PRINCIPLES
RECEPTOR DESENSITIZATION AND
REGULATION OF RECEPTORS
Receptors not only initiate regulation of biochemical
events and physiological function but also are themselves
subject to many regulatory and homeostatic controls.
These controls include regulation of the synthesis
and degradation of the receptor, covalent modification,
association with other regulatory proteins, and
relocalization within the cell. Transducer and effector
proteins are regulated similarly. Modulatory inputs may
come from other receptors, directly or indirectly, and
receptors are almost always subject to feedback regulation
by their own signaling outputs.
Continued stimulation of cells with agonists generally
results in a state of desensitization (also referred
to as adaptation, refractoriness, or down-regulation)
such that the effect that follows continued or subsequent
exposure to the same concentration of drug is diminished.
This phenomenon, called tachyphylaxis, occurs
rapidly and is important therapeutically; an example is
attenuated response to the repeated use of β adrenergic
receptor agonists as bronchodilators for the treatment
of asthma (Chapters 12 and 36).
Desensitization can result from temporary inaccessibility
of the receptor to agonist or from fewer
receptors being synthesized and available at the cell
surface (e.g., down-regulation of receptor number).
Phosphorylation of GPCR receptors by specific GPCR
kinases (GRKs) plays a key role in triggering rapid
desensitization. Phosphorylation of agonist-occupied
GPCRs by GRKs facilitates the binding of cytosolic
proteins termed arrestins to the receptor, resulting in
the uncoupling of G protein from the receptor (Moore
et al., 2007). The β-arrestins recruit proteins, such as
PDE4, that limit cyclic AMP signaling, and clathrin and
β2-adaptin, that promote sequestration of receptor from
the membrane (internalization), thereby providing a
scaffold that permits additional signaling steps.
Conversely, supersensitivity to agonists also frequently
follows chronic reduction of receptor stimulation.
Such situations can result, e.g., following
withdrawal from prolonged receptor blockade (e.g., the
long-term administration of β adrenergic receptor antagonists
such as metoprolol) or in the case where chronic
denervation of a preganglionic fiber induces an increase
in neurotransmitter release per pulse, indicating postganglionic
neuronal supersensitivity. Supersensitivity
can be the result of tissue response to pathological conditions,
such as occurs in cardiac ischemia due to the
synthesis and recruitment of new receptors to the surface
of the myocyte.
It seems likely that effects of several classes of
CNS-active agents depend on similar agonist- and
antagonist-induced changes in receptor-effector systems
(Chapters 14, 15, and 18).
Diseases Resulting from Receptor Malfunction. Alteration in
receptors and their immediate signaling effectors can be the cause of
disease. The loss of a receptor in a highly specialized signaling system
may cause a relatively limited, if dramatic, phenotypic disorder
(e.g., deficiency of the androgen receptor and testicular feminization
syndrome; Chapter 41). Deficiencies in widely employed signaling
pathways have broad effects, as are seen in myasthenia gravis
and some forms of insulin-resistant diabetes mellitus, which result
from autoimmune depletion of nicotinic cholinergic receptors
(Chapter 11) or insulin receptors (Chapter 43), respectively. The
expression of constitutively active, aberrant, or ectopic receptors,
effectors, and coupling proteins potentially can lead to supersensitivity,
subsensitivity, or other untoward responses (Smit et al., 2007).
Among the most significant events is the appearance of aberrant