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

α 2
and postjunctional α 1
adrenergic receptors has been
abandoned in favor of a pharmacological and functional
classification (Tables 8–6 and 8–7).
Cloning revealed additional heterogeneity of both α 1
and α 2
adrenergic receptors (Bylund, 1992). There are three pharmacologically
defined α 1
receptors (α 1A
, α 1B
, and α 1D
) with distinct
sequences and tissue distributions, and three cloned subtypes of
α 2
receptors (α 2A
, α 2B
, and α 2C
) (Table 8–6). A fourth type of
α 1
receptor, α 1L
AR, has been defined on the basis of a low affinity
for a number of selective antagonists including prazosin (Hieble,
2007). This phenotype could be of physiological significance since
the α 1L
profile has been identified in a variety of tissues across a
number of different species, where it appears to regulate smooth
muscle contractility in the vasculature and lower urinary tract. It also
appears (at least in the mouse prostate smooth muscle) to be dependent
upon expression of the α 1A
AR gene product. Moreover, an intact cellular
environment is important for the manifestation of the α 1L
AR
phenotype in vivo. Despite intense efforts, α 12
AR has not been
cloned and it is doubtful that α 1L
is a discrete AR (Hieble, 2007).
Owing to the lack of sufficiently subtype-selective ligands,
the precise physiological function and therapeutic potential of the
subtypes of adrenergic receptors have not been elucidated fully.
Great advances in our understanding have been made through the
use of genetic approaches using transgenic and receptor knockout
experiments in mice (discussed later). These mouse models have
been used to identify the particular receptor subtypes and pathophysiological
relevance of individual adrenergic receptors subtypes
(Philipp and Hein, 2004; Tanoue et al., 2002a, 2002b; Xiao
et al., 2006).
Molecular Basis of Adrenergic Receptor Function. All
of the adrenergic receptors are GPCRs that link to heterotrimeric
G proteins. Each major type shows preference
for a particular class of G proteins, i.e., α 1
to G q
,
α 2
to G i
, and β to G s
(Table 8–6). The responses that
follow activation of all types of adrenergic receptors
result from G protein–mediated effects on the generation
of second messengers and on the activity of ion
channels, as discussed in Chapter 3. The pathways
overlap broadly with those discussed for muscarinic
acetylcholine receptors and are summarized in Table
8–6 (Drake et al., 2006; Park et al., 2008).
Structure of Adrenergic Receptors. Adrenergic receptors
constitute a family of closely related proteins that
are related both structurally and functionally to GPCRs
for a wide variety of other hormones and neurotransmitters
(see Chapter 3). Ligand binding, site-directed
labeling, and mutagenesis have revealed that the conserved
membrane-spanning regions are crucially
involved in ligand binding (Hutchins, 1994; Strader
et al.,1994). These regions appear to create a ligandbinding
pocket analogous to that formed by the membrane-spanning
regions of rhodopsin to accommodate
the covalently attached chromophore, retinal, with
molecular models placing catecholamines either
horizontally (Strader et al., 1994) or perpendicularly
(Hutchins, 1994) in the bilayer. The crystal structure of
mammalian rhodopsin confirms a number of predictions
about the structure of GPCRs (Palczewski et al.,
2000).
a Adrenergic Receptors. The three β receptors share
~60% amino acid sequence identity within the
presumed membrane-spanning domains where the
ligand-binding pocket for epinephrine and norepinephrine
is found. Based on results of site-directed mutagenesis,
individual amino acids in the β 2
receptor that
interact with each of the functional groups on the catecholamine
agonist molecule have been identified.
β Receptors regulate numerous functional
responses, including heart rate and contractility, smooth
muscle relaxation, and multiple metabolic events in
numerous tissues including adipose and hepatic cells
and skeletal muscle (Lynch and Ryall, 2008)
(Table 8–1). All three of the β receptor subtypes (β 1
, β 2
,
and β 3
) couple to G s
and activate adenylyl cyclase
(Table 8–7). However, recent data suggest differences in
downstream signals and events activated by the three
β receptors (Lefkowitz, 2000; Ma and Huang, 2002).
Catecholamines promote β receptor feedback regulation,
that is, desensitization and receptor downregulation
(Kohout and Lefkowitz, 2003). β Receptors
differ in the extent to which they undergo such regulation,
with the β 2
receptor being the most susceptible.
Stimulation of β adrenergic receptors leads to the accumulation
of cyclic AMP, activation of the PKA, and
altered function of numerous cellular proteins as a
result of their phosphorylation (Chapter 3). In addition,
G s
can enhance directly the activation of voltagesensitive
Ca 2+ channels in the plasma membrane of
skeletal and cardiac muscle.
Several reports demonstrate that β 1
, β 2
, and β 3
receptors can
differ in their intracellular signaling pathways and subcellular location
(Brodde et al., 2006; Violin and Lefkowitz, 2007; Woo, et al.,
2009). While the positive chronotropic effects of β 1
receptor activation
are clearly mediated by G s
in myocytes, dual coupling of β 2
receptors to G s
and G i
occurs in myocytes from newborn mice.
Stimulation of β 2
receptors caused a transient increase in heart rate
that is followed by a prolonged decrease. Following pretreatment with
pertussis toxin, which prevents activation of G i
, the negative
chronotropic effect of β 2
activation is abolished. It is thought that
these specific signaling properties of β receptor subtypes are linked
to subtype-selective association with intracellular scaffolding and signaling
proteins (Baillie and Houslay, 2005). β 2
Receptors normally
are confined to caveolae in cardiac myocyte membranes. The activation
205
CHAPTER 8
NEUROTRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR NERVOUS SYSTEMS