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

Table 8–6
Characteristics for Adrenergic Receptor Subtypes (Continued)
GENE LOCATION
IN HUMAN G-PROTEIN PRINCIPLE TISSUE SUBTYPE
SUBTYPE a CHROMOSOME COUPLING EFFECTORS LOCALIZATION DOMINANT EFFECTS b
β 1
10q240q26 Gα s
Activation of AC Heart • Predominant receptor in
↑ cAMP Kidney heart producing positive
↑ PKA activation Adipocytes inotropic and
Activation of L type Skeletal muscle chronotropic effects
Ca 2+ channels Olfactory nucleus
Cortex
Cerebellar nuclei
Brain stem
Spinal cord
c
β 2
531-q32 Gα s
Activation of AC Heart, Lung • Predominant receptor in
↑ cAMP Blood vessels smooth muscle relaxation
↑ PKA activation Bronchial and GI • Skeletal muscle hypertrophy
Activation of Ca 2+ smooth muscle
channels
Kidney
Skeletal muscle
Olfactory bulb
Piriform cortex
Cortex
Hippocampus
c,d
β 3
8p12-p11.2 Gα s
Activation of AC Adipose tissue • Predominant receptor
↑ cAMP GI tract producing metabolic
↑ PKA activation Heart effects
Activation of Ca 2+
channels
a
At least three subtypes each of α 1
and α 2
adrenergic receptors are known, but distinctions in their mechanisms of action have not been clearly
defined.
b
In some species (e.g., rat), metabolic responses in the liver are mediated by α 1
adrenergic receptors, whereas in others (e.g., dog) β 2
adrenergic
receptors are predominantly involved. Both types of receptors appear to contribute to responses in human beings.
c
β Receptor coupling to cell signaling can be more complex. In addition to coupling to G s
to stimulate AC, β 2
receptors can activate signaling via a
GRK/β-arrestin pathway (Violin and Lefkowitz, 2007). β 2
and β 3
receptors can couple to both G s
and G i
in a manner that may reflect agonist stereochemistry
(Woo et al., 2009). See also Chapter 12.
d
Metabolic responses in adipocytes and certain other tissues with atypical pharmacological characteristics may be mediated by this subtype of receptor.
Most β adrenergic receptor antagonists (including propranolol) do not block these responses.
AC, adenylyl cyclase; Epi, epinephrine; NE, norepinephrine; Iso, isoproterenol; GI, gastrointestinal; GU, genitourinary.
feedback-inhibitory effect of NE on its release from
nerve terminals is mediated by α receptors that are
pharmacologically distinct from the classical postsynaptic
α receptors. Accordingly, these presynaptic α
adrenergic receptors were designated α 2
, whereas the
postsynaptic “excitatory” α receptors were designated
α 1
(Langer, 1997). Compounds such as clonidine are
more potent agonists at α 2
than at α 1
receptors; by contrast,
phenylephrine and methoxamine selectively activate
postsynaptic α 1
receptors. Although there is little
evidence to suggest that α 1
adrenergic receptors function
presynaptically in the autonomic nervous system,
it is now clear that α 2
receptors also are present at
postjunctional or nonjunctional sites in several tissues.
For example, stimulation of postjunctional α 2
receptors
in the brain is associated with reduced sympathetic
outflow from the CNS and appears to be
responsible for a significant component of the antihypertensive
effect of drugs such as clonidine (Chapter 12).
Thus, the anatomic concept of prejunctional