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

kinases such as the calmodulin-dependent myosin
light-chain kinase; phosphorylation of the light chain
of myosin is associated with the development of tension
(see Chapter 3). In contrast, the increased concentration
of intracellular Ca 2+ that result from stimulation
of α 1
receptors in GI smooth muscle causes hyperpolarization
and relaxation by activation of Ca 2+ -dependent
K + channels (McDonald et al., 1994).
As with α 2
receptors, there is considerable evidence demonstrating
that α 1
receptors activate MAPKs and other kinases such as
PI3 kinase leading to important effects on cell growth and proliferation
(Dorn and Brown, 1999; Gutkind, 1998). For example,
prolonged stimulation of α 1
receptors promotes growth of cardiac
myocytes and vascular smooth muscle cells. The α 1A
receptor is the
predominant receptor causing vasoconstriction in many vascular
beds, including the following arteries: mammary, mesenteric,
splenic, hepatic, omental, renal, pulmonary, and epicardial coronary.
It is also the predominant subtype in the vena cava and the saphenous
and pulmonary veins (Michelotti et al., 2001). Together with the
α 1B
receptor subtype, it promotes cardiac growth and structure. The
α 1B
receptor subtype is the most abundant subtype in the heart,
whereas the α 1D
receptor subtype is the predominant receptor causing
vasoconstriction in the aorta. There is evidence to support the
idea that α 1B
receptors mediate behaviors such as reaction to novelty
and exploration and are involved in behavioral sensitizations and in
the vulnerability to addiction (see Chapter 24).
Adrenergic Receptor Polymorphism. Numerous polymorphisms
and slice variants of adrenergic receptors continue to be identified.
Receptors α 1A
, α 1B
and β 1D
, β 1
, and β 2
are polymorphic. Such polymorphisms
in these adrenergic receptors could result in altered
physiological responses to activation of the sympathetic nervous system,
contribute to disease states and alter the responses to adrenergic
agonists and/or antagonists (Brodde, 2008). Knowledge of the
functional consequences of specific polymorphisms could theoretically
result in the individualization of drug therapy based on a
patient’s genetic makeup and could explain marked inter-individual
variability within the human population.
Localization of Adrenergic Receptors. Presynaptically
located α 2
and β 2
receptors fulfill important roles in the
regulation of neurotransmitter release from sympathetic
nerve endings. Presynaptic α 2
receptors also may mediate
inhibition of release of neurotransmitters other than
norepinephrine in the central and peripheral nervous
systems. Both α 2
and β 2
receptors are located at postsynaptic
sites (Table 8–6), such as on many types of
neurons in the brain. In peripheral tissues, postsynaptic
α 2
receptors are found in vascular and other smooth
muscle cells (where they mediate contraction),
adipocytes, and many types of secretory epithelial cells
(intestinal, renal, endocrine). Postsynaptic β 2
receptors
can be found in the myocardium (where they mediate
contraction) as well as on vascular and other smooth
muscle cells (where they mediate relaxation) and
skeletal muscle (where they can mediate hypertrophy).
Indeed, most normal human cell types express β 2
receptors.
Both α 2
and β 2
receptors may be situated at sites
that are relatively remote from nerve terminals releasing
NE. Such extrajunctional receptors typically are
found on vascular smooth muscle cells and blood elements
(platelets and leukocytes) and may be activated
preferentially by circulating catecholamines, particularly
epinephrine.
In contrast, α 1
and β 1
receptors appear to be
located mainly in the immediate vicinity of sympathetic
adrenergic nerve terminals in peripheral target organs,
strategically placed to be activated during stimulation of
these nerves. These receptors also are distributed
widely in the mammalian brain (Table 8–6).
The cellular distributions of the three α 1
and three
α 2
receptor subtypes still are incompletely understood.
In situ hybridization of receptor mRNA and receptor
subtype-specific antibodies indicates that α 2A
receptors
in the brain may be both pre- and postsynaptic. These
findings and other studies indicate that this receptor subtype
functions as a presynaptic autoreceptor in central
noradrenergic neurons (Aantaa et al., 1995; Lakhlani et
al., 1997). Using similar approaches, α 1A
mRNA was
found to be the dominant subtype message expressed in
prostatic smooth muscle (Walden et al., 1997).
Refractoriness to Catecholamines. Exposure of
catecholamine-sensitive cells and tissues to adrenergic
agonists causes a progressive diminution in their capacity
to respond to such agents. This phenomenon, variously
termed refractoriness, desensitization, or tachyphylaxis,
can limit the therapeutic efficacy and duration of action of
catecholamines and other agents (Chapter 3). The mechanisms
are incompletely understood. They have been
studied most extensively in cells that synthesize cyclic
AMP in response to β 2
receptor agonists.
Multiple mechanisms are involved in desensitization,
including rapid events such as receptor phosphorylation
by both G-protein receptor kinases (GRKs) and
by signaling kinases such as PKA and PKC, receptor
sequestration, uncoupling from G proteins, and activation
of specific cyclic nucleotide phosphodiesterases.
More slowly occurring events also are seen, such as
receptor endocytosis, which decreases receptor number.
An understanding of the mechanisms involved in
regulation of GPCR desensitization has developed over
the last few years (Kohout and Lefkowitz, 2003; Violin
and Lefkowitz, 2007). Such regulation is very complex
and exceeds the simplistic model of GPCR phosphorylation
by GRKs followed by arrestin binding and
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CHAPTER 8
NEUROTRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR NERVOUS SYSTEMS