Vol. 283, Issue 2, R287-R295, August 2002
INVITED REVIEW
Physiological significance of 
2-adrenergic
receptor subtype diversity: one receptor is not enough
Melanie
Philipp,
Marc
Brede, and
Lutz
Hein
Institut für Pharmakologie und Toxikologie,
Universität Würzburg, 97078 Würzburg,
Germany
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ABSTRACT |
2-Adrenergic receptors
mediate part of the diverse biological effects of the endogenous
catecholamines epinephrine and norepinephrine. Three distinct subtypes
of 2-adrenergic receptors, 2A,
2B, 2C, have been identified from
multiple species. Because of the lack of sufficiently subtype-selective
ligands, the specific biological functions of these receptor subtypes
were largely unknown until recently. Gene-targeted mice carrying
deletions in the genes encoding for individual
2-receptor subtypes have added important new insight into the physiological significance of adrenergic receptor diversity. Two different strategies have emerged to regulate adrenergic signal transduction. Some biological functions are controlled by two counteracting 2-receptor subtypes, e.g.,
2A-receptors decrease sympathetic outflow and blood
pressure, whereas the 2B-subtype increases blood
pressure. Other biological functions are regulated by synergistic
2-receptor subtypes. The inhibitory presynaptic feedback
loop that tightly regulates neurotransmitter release from adrenergic
nerves also requires two receptor subtypes, 2A and
2C. Similarly, nociception is controlled at several
levels by one of the three 2-receptor subtypes. Further
investigation of the specific function of 2-subtypes
will greatly enhance our understanding of the relevance of closely
related receptor proteins and point out novel therapeutic strategies
for subtype-selective drug development.
adrenergic receptors; transgenic mice; gene targeting
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INTRODUCTION |
ADRENERGIC RECEPTORS FORM the interface
between the endogenous catecholamines epinephrine and norepinephrine
and a wide array of target cells in the body to mediate the biological
effects of the sympathetic nervous system. To date, nine distinct
adrenergic receptor subtypes have been cloned from several species:
1A, 1B, 1D,
2A, 2B, 2C,
1, 2, and 3
(11). For many of these receptors, their precise
physiological functions and their therapeutic potential have not been
fully elucidated. Only for -adrenergic receptors have sufficiently
subtype-selective ligands been developed that have helped to identify
the physiological significance of 1-, 2-,
and 3-receptors, some of which have entered clinical medicine. Selective agonists for the 2-adrenergic
receptor play an important role in asthma therapy, whereas
1-receptor antagonists are first-line medication for
patients with hypertension, coronary heart disease, or chronic heart
failure (8, 20, 50). For 1-receptors,
subtype-selective ligands that can diminish the symptoms of benign
prostate hyperplasia without causing hypotension have just entered
clinical therapy (33). Despite the fact that 2-adrenergic receptors serve a number of physiological
functions in vivo and have great therapeutic potential, no sufficiently subtype-selective ligands are clinically available yet. Despite this fact, non-subtype-selective 2-receptor agonists
like clonidine, medetomidine, and brimonidine are being used to
treat patients with hypertension, glaucoma, tumor pain, postoperative
pain, and shivering or to block the symptoms of sympathetic
overactivity during drug withdrawal (66). Unfortunately,
the fields of therapeutic application and unwanted side effects are
overlapping, e.g., 2-receptor-mediated sedation is an
important problem for treatment of hypertension. Severe side effects
are one reason why 2-receptor agonists are only
second-line antihypertensive agents. It is tempting to speculate that
2-receptor-mediated therapy could be greatly improved
and advanced if receptor subtype-selective ligands were available. However, before developing specific ligands, the therapeutic targets have to be identified. Recently, transgenic and gene-targeted mouse
models have added considerable information about individual adrenergic
receptor subtypes (15, 25, 37, 39, 53, 54). This review
focuses on the specific functions of the three
2-adrenergic receptor subtypes in mouse models carrying
targeted deletions in the genes encoding for
2-receptors.
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2-ADRENERGIC RECEPTOR GENES |
So far, three distinct genes have been identified from several
species that encode for separate subtypes of
2-adrenergic receptors (11). From these
genes, three 2-receptors are synthesized, termed
2A, 2B, and 2C. The
pharmacological ligand binding characteristics of the
2A-subtype differ significantly between different
species, thus giving rise to the pharmacological subtypes
2A in humans, rabbits, and pigs and 2D in
rats, mice, and guinea pig (11). This species variation is
at least in part due to a single amino acid variation in the fifth
transmembrane domain of the 2A-receptor that renders
this receptor less sensitive to yohimbine binding (34).
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GENE-TARGETED MICE LACKING INDIVIDUAL
2-RECEPTOR SUBTYPES |
Several mouse lines have been established by gene targeting that
do not express functional 2-adrenergic receptors
(2, 35, 36). All of these mice developed apparently
normally, although mice lacking 2B-adrenergic receptors
were not born at the expected Mendelian ratios, indicating that this
receptor may play a role during embryonic development (13,
35).
In addition, a point mutation has been introduced into the
2A-receptor gene (2-D79N) to evaluate the
physiological role of separate intracellular signaling pathways of this
receptor in vivo (38). The D79N mutation substitutes
asparagine for an aspartate residue at position 79, which is predicted
to lie within the second transmembrane region of the
2A-receptor and is highly conserved among G
protein-coupled receptors. In vitro, the 2A-D79N receptor has been shown to be deficient in coupling to K+
channel activation (76). However, in vivo this point
mutation was found to be deficient in K+ current activation
and Ca2+ channel inhibition (32).
Surprisingly, the density of 2A-D79N receptors in the
mouse brain was decreased to ~20% of the normal level
(38). Thus, in most (but not all) functional tests, the 2A-D79N receptor had characteristics resembling a
functional "knockout" of the 2A-receptor
(40). One important exception was the observation that the
presynaptic inhibitory function of the 2A-D79N receptor
was normal or only slightly blunted in intact tissues (2).
Most likely, the decreased expression of 2A-D79N receptors in vivo rather than a selective defect in receptor signaling seems to be important for the "functional knockout." At the
presynaptic side, a high number of spare receptors is characteristic
for 2-receptor function, i.e., activation of very few
2-receptors results in maximal presynaptic inhibition of
transmitter release (1). Thus the reduced number of
presynaptic 2A-D79N receptors may still be sufficient
for presynaptic control, whereas the decreased receptor density may
compromise receptor signal transduction at other sites with a smaller
receptor reserve.
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WHICH 2-RECEPTOR SUBTYPE IS THE
PRESYNAPTIC REGULATOR? |
2-Adrenergic receptors were initially characterized
as presynaptic receptors that serve as parts of a negative feedback
loop to regulate the release of norepinephrine (71). Soon
it was shown that 2-receptors are not restricted to
presynaptic locations but also have postsynaptic functions (Fig.
1A). With the use of an array
of pharmacological antagonists, the 2A-receptor was predicted to be the major inhibitory presynaptic receptor regulating release of norepinephrine from sympathetic neurons as part of a
feedback loop (82). However, in some tissues, the
2C-receptors were considered to be in the inhibitory
presynaptic receptor (55).
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Fig. 1.
Presynaptic 2-adrenergic receptor subtypes.
A: in sympathetic or central adrenergic nerves,
2A- and 2C-receptors operate as
inhibitory autoreceptors to control neurotransmitter release.
2B-Receptors are located on postsynaptic cells to
mediate the effects of catecholamines released from sympathetic nerves,
e.g., vasoconstriction. B: presynaptic 2A-
and 2C-receptors can be distinguished functionally. In
intact tissue slices from mouse heart atria,
2A-receptors inhibit norepinephrine release from
sympathetic nerves primarily at high stimulation frequencies, whereas
the 2C-receptor can also operate at very low frequencies
to control basal norepinephrine release. WT, wild type. Data adapted
from Ref. 26.
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With the genetic deletion of individual 2-receptor genes
in mice, this classification of the presynaptic autoreceptor subtype was challenged. In mice lacking the 2A-subtype,
presynaptic feedback regulation was severely impaired but not
abolished, indicating that indeed the 2A-receptor is the
major autoreceptor in sympathetic neurons (Fig. 1A)
(2, 26). Most surprisingly, the 2C-receptor turned out to function as an additional presynaptic regulator in all
central and peripheral nervous tissues investigated (Fig. 1A) (2, 9, 26, 70, 79, 80). However, the
relative contributions of 2A- and
2C-receptors differed between central and peripheral
nerves, with the 2C-receptor being more prominent in
sympathetic nerve endings than in central adrenergic neurons. 2A- and 2C-receptors differ in their time
course of expression after birth (65). While
2A-mediated autoinhibition of neurotransmitter release
is already operative immediately after birth, the
2C-receptor function is established later in mice
(65).
Furthermore, the 2-autoreceptor subtypes could be
distinguished functionally: 2A-receptors inhibited
transmitter release significantly faster and at higher action potential
frequencies than the 2C-receptors (Fig. 1B)
(9, 26, 62). When 2A- and
2C-receptors were stably expressed together with N-type
Ca2+ channels or with G protein-coupled inwardly rectifying
K+ (GIRK) channels, no differences in the
activation kinetics of these two receptor subtypes were detected at
identical levels of receptor expression (10). However,
when receptor GIRK channel deactivation after removal of norepinephrine
was followed, the 2C-receptor was found to be active for
a significantly longer time than the 2A-subtype
irrespective of the level of receptor expression. This difference in
2-receptor deactivation kinetics could be explained by
the higher affinity of norepinephrine for the 2C- than
for the 2A-receptor subtype (10). This
property makes the 2C-receptor particularly suited to
control neurotransmitter release at low action potential frequencies
(Fig. 1) (26). In contrast, the 2A-receptor
seems to operate primarily at high stimulation frequencies in
sympathetic nerves and may thus be responsible for controlling
norepinephrine release during maximal sympathetic activation.
2-Adrenergic receptors not only inhibit release of their
own neurotransmitters (autoreceptors) but can also regulate the exocytosis of a number of other neurotransmitters in the central and
peripheral nervous system. In the brain, 2A- and
2C-receptors can inhibit dopamine release in basal
ganglia (9) as well as serotonin secretion in mouse
hippocampal or brain cortex slices (61). In contrast, the
inhibitory effect of 2-agonists on gastrointestinal motility was mediated solely by the 2A-subtype
(63).
Part of the functional differences between 2A- and
2C-receptors may be explained by their distinct
subcellular localization patterns (Fig.
2) (14, 47, 86, 87). In
cultured sympathetic neurons from newborn mice, functional presynaptic
2-receptors develop to inhibit voltage-dependent
Ca2+ channels and norepinephrine release (77,
78). In sympathetic neurons, only the 2A-subtype
but not the 2C-receptor contributed to inhibition of
neurotransmitter release (81). Remarkably, inhibition of
Ca2+ channels located on neuronal cell bodies and dendrites
was mediated by both 2A- and
2C-receptors. Thus 2C-receptors in
neurons may require a specific itinerary to guide their expression to axonal termini.
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Fig. 2.
2-Adrenergic receptors differ in their trafficking
itineraries in cells. When expressed in rat1 fibroblasts,
2A- and 2B-receptors are targeted to the
plasma membrane (immunofluorescence images). On stimulation with
agonist, only 2B-receptors are reversibly internalized
into endosomes. 2C-Receptors are primarily localized in
an intracellular membrane compartment, from where the
2C-receptors can be translocated to the cell surface
after exposure to cold temperature (29).
Bottom: murine 2-receptor subtypes after
transient transfection into rat1 fibroblasts as described previously
(14). Arrows point to 2-receptors residing
in the plasma membrane; arrowhead marks 2C-receptors in
an intracellular compartment.
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BLOOD PRESSURE REGULATION |
2-Receptors are involved in the control of blood
pressure homeostasis at a number of locations (Fig.
3). Nonselective activation of
2-receptors usually leads to a biphasic blood pressure
response: after a short hypertensive phase that is more pronounced
after rapid intravenous injection, arterial pressure falls below the baseline. After oral application of 2-agonists, the
hypotensive action prevails and is being used to treat elevated blood
pressure in hypertensive patients. Interestingly, the two phases of the pressure response are mediated by two different
2-receptor subtypes in vivo: 2B-receptors
are responsible for the initial hypertensive phase, whereas the
long-lasting hypotension is mediated by 2A-receptors (2, 35, 38). Thus the 2A-receptor is a
therapeutic target for subtype-selective antihypertensive agents. The
blockade of 2-receptors may be of therapeutic benefit in
patients with atherosclerotic coronary arteries (3),
whereas it is still unknown which 2-receptor subtype is
responsible for the vasoconstriction in humans. An insertion/deletion
polymorphism with decreased receptor desensitization of the
2B-receptor subtype is associated with an increased risk for acute coronary events (69).
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Fig. 3.
Integrative regulation of blood pressure by different
2-adrenergic receptor subtypes. Activation of
2A-receptors leads to a decrease in blood pressure by
inhibiting central sympathetic outflow as well as norepinephrine
release from sympathetic nerves (2, 38).
2B-Receptors may counteract this effect by causing
direct vasoconstriction and salt-induced hypertension (22,
35). 2C-Receptors participate in
2-mediated vasoconstriction after exposure to cold
temperature (12).
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Some evidence indicates that 2A-receptors also
participate to a smaller degree in the vasoconstrictor action of
2-agonists in mice (38). Bolus injection of
norepinephrine caused transient hypertension in wild-type mice and in
2B- and 2C-deficient mice but not in mice
lacking the 2A-receptor (16). Vascular
2-receptor subtypes may be differentially distributed
between vascular beds. When 2-agonists were injected
into the carotid artery, most of the hypertensive response to
2-activation was mediated by the 2B-receptor (35), whereas injection into
the femoral artery showed a blunted hypertensive effect in mice with
the 2A-D79N receptor (38). In some
arteries, 2-mediated vasoconstriction may even
predominate over 1-receptor-induced contraction, and decreased -receptor responsiveness may contribute to elevated blood
flood in tissue inflammation, e.g., arthritis (45).
In addition to its role as a vasoconstrictor, the
2B-receptor seems to be required for the development of
salt-sensitive hypertension (Fig. 3) (22, 41-43).
Nephrectomy followed by Na+ loading has been established as
a model of hypertension in mice (22). In this system, the
development of hypertension depends on increased vasopressin release
and sympathetic activation (21). Bilateral nephrectomy and
saline infusion raised blood pressure in wild-type and in
2A- and 2C-receptor-deficient mice.
However, in 2B-deficient animals a small fall in
arterial pressure was observed (41). Recent experiments
with 2B-antisense oligonucleotide injection into the
lateral brain ventricle suggest that a central 2B-adrenergic receptor is necessary for induction of
salt-dependent hypertension (31).
Under certain conditions, even the 2C-receptor subtype
may contribute to vascular regulation: when kept below 37°C for a while, cutaneous arteries of the mouse tail show an
2C-receptor-dependent vasoconstriction that could not be
observed when the vessel segments were incubated at body temperature
(12). This finding may be of great therapeutic interest
for the treatment of Raynaud's disease. Patients with Raynaud's
phenomenon suffer from severe periods of vasoconstriction of their
fingers and toes that are usually triggered by exposure to cold.
Treatment of these patients with 2-adrenergic
antagonists diminished the vasoconstriction (19). Interestingly, silent 2C-receptors may be translocated
from an intracellular receptor pool to the cell surface on cooling
(Fig. 2) (29). This phenomenon has been observed in human
embryonic kidney (HEK-293) cells transfected with recombinant
2C-receptors: cooling of cells to 28°C evoked a
redistribution of 2C-receptors from the Golgi apparatus
to the plasma membrane within 1 h (29). Thus
inhibition of 2C-receptors may prove an effective
treatment for Raynaud's phenomenon.
In addition to these vascular and central neuronal mechanisms, renal
2-receptors may be involved in the long-term regulation of blood pressure and fluid and electrolyte homeostasis (48, 49). Activation of renal vascular 2B-receptors
may lead to an increase in medullary NO production and thus counteract
the vasoconstrictor effects of norepinephrine in the renal medulla (90). Via this mechanism, 2B-receptors may
be essential in the regulation of renal medullary blood flow and oxygen supply.
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ANALGESIA |
2-Agonists are potent analgesics, and they can
potentiate the analgesic effect of opioids (75, 85, 88).
Recent data indicate that all three 2-receptor subtypes
are involved in the regulation of pain perception in the mouse (Fig.
4).
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Fig. 4.
Three 2-adrenergic receptor subtypes are involved in
the control of pain perception in mice. A: schematic
representation of 2-receptor subtypes controlling spinal
nociception. B: distribution of 2-receptors
in the mouse spinal cord by autoradiography with a
non-subtype-selective 2-receptor antagonist
(9). In the spinal cord, the highest density of
2-adrenergic receptors was observed in the superficial
layers of the dorsal horns (B, arrows). Here, all 3 2-receptor subtypes control incoming nociceptive
impulses: 2A-receptors are required for the analgesic
effect of systemically applied 2-agonists, spinal
2C-receptors contribute to the moxonidine-mediated
analgesia, and 2B-receptors are required for the spinal
antinociceptive effect of nitrous oxide. See text for references. The
autoradiogram shown in B was kindly provided by K. Hadamek,
Würzburg, Germany.
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The 2A-receptor mediates the antinociception induced by
systemically applied 2-agonists, including clonidine and
dexmedetomidine (18, 74). Compared with control mice,
2-agonists were completely ineffective as an
antinociceptive agent in the tail immersion or substance P test in
2A-D79N mice (27). The
2A-D79N mutation also blocked the synergy seen in
wild-type mice between 2-agonists and delta-opioid
agonists (74). Interestingly,
2A-receptor-deficient mice showed a reduced
antinociceptive effect to isoflurane (30). However, not
all 2-receptor agonists required functional
2A-receptors for their antinociceptive effect (Fig. 4).
The imidazoline/2-receptor ligand moxonidine caused
spinal antinociception that was at least partially dependent on
2C-receptors (17).
Surprisingly, nitrous oxide, which is used as a potent inhalative
analgesic during anesthesia, requires the 2B-subtype for its antinociceptive effect (Fig. 4) (23, 60). Supraspinal opioid receptors and spinal 2B-receptors are involved in
the analgesic pathway for nitrous oxide. Activation of endorphin
release in the periaqueductal gray by nitrous oxide stimulates a
descending noradrenergic pathway that releases norepinephrine onto
2B-receptors in the dorsal horn of the spinal cord
(89). In mice lacking 2B-receptors, the
analgesic effect of nitrous oxide was completely abolished
(60).
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SEDATION |
2-Agonists are used in the postoperative phase or
in intensive care as sedative, hypnotic, and analgesic agents
(44, 66). The sedative effects of
2-agonists in mice are solely mediated by the
2A-receptor subtype (32).
2A-D79N mice showed no sedative response to the
2-agonist dexmedetomidine (32). In
contrast, mice lacking the 2B- or
2C-receptors did not differ in their sedative response
from wild-type control mice (27, 59). Similarly, the
anesthetic-sparing effect of 2-agonists was completely
abolished in 2A-D79N mice (32).
The hypnotic effect of 2-agonists is most likely
mediated in the locus ceruleus. Neurons of the locus ceruleus express
2A-adrenergic receptors at very high density
(84). Furthermore, 2A-antisense oligonucleotide injection into the locus ceruleus in rats attenuated the sedative effects of exogenous 2-agonists
(46).
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BEHAVIOR |
Because of their widespread distribution in the central nervous
system, 2-receptors affect a number of behavioral
functions (5, 56, 57, 67). In particular, the
2C-receptor subtype has been demonstrated to inhibit the
processing of sensory information in the central nervous system of the
mouse (for a recent review, see Ref. 64). Activation of
2-receptors also resulted in locomotor inhibition. While
direct activation of 2-receptors by dexmedetomidine did
not alter spontaneous motor activity in
2C-receptor-deficient mice (59),
D-amphetamine stimulated locomotor activity to a greater
extent in 2C-deficient mice than in wild-type mice
(58).
Mice overexpressing 2C-receptors were impaired in
spatial and nonspatial water maze tests, and an
2-antagonist fully reversed the water maze escape defect
in these mice (4-6). The 2-agonist dexmedetomidine increased swimming distance more effectively in wild-type mice than in 2C-receptor-deficient mice
(4). Activation of 2C-receptors disrupts
execution of spatial and nonspatial search patterns, whereas
stimulation of 2A- and/or 2B-receptors may actually improve spatial working memory in mice (7).
It may be concluded that novel agonists devoid of
2C-receptor affinity can modulate cognition more
favorably than non-subtype-selective drugs.
Altered startle reactivity and attenuation of the inhibition of the
startle reflex by an acoustic prepulse have been observed in
schizophrenia, and disrupted prepulse inhibition has frequently been
used as an animal model for drug antipsychotic drug development. Interestingly, 2C-receptor-deficient mice had enhanced
startle responses, diminished prepulse inhibition, and shortened attack latency in the isolation-aggression test (57). Thus drugs
acting via the 2C-receptor may have therapeutic value in
disorders associated with enhanced startle responses and sensorimotor
gating deficits, such as schizophrenia, attention deficit disorder,
posttraumatic stress disorder, and drug withdrawal. In addition to the
2C-subtype, the 2A-receptor has an
important role in modulating behavioral functions. Experiments using
gene-targeted mice indicate that the 2A-receptor may
play a protective role in some forms of depression and anxiety, and
this receptor may mediate part of the antidepressant effects of
imipramine (67). Thus 2A- and
2C-receptors complement each other to integrate central
nervous system function and behavior.
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OTHER PHYSIOLOGICAL FUNCTIONS AND PHARMACOLOGICAL TARGETS |
2-Receptors are involved in the regulation of body
temperature as well as seizure threshold. Activation of central
2A-receptors causes a powerful antiepileptogenic effect
in mice (28). Two receptor subtypes, 2A and
2C, may be involved in the hypothermic action of
2-agonists (27, 59). Another important
function of 2-agonists is their inhibitory effect on
intraocular pressure. The 2-agonists apraclonidine and
brimonidine are currently being used to lower intraocular pressure in
patients with glaucoma (52, 68). In adipose tissue,
2-receptors inhibit lipolysis (72, 73) and
2-receptors are potential targets for the treatment of
obesity. Mice expressing human 2-receptors in fat tissue
in vivo, in the absence of 3-adrenergic receptors,
developed high-fat diet-induced obesity (83). However, the
precise role of individual 2-receptor subtypes in the
control of lipolysis is unknown at present.
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CONCLUSIONS |
Genetic deletion of 2-adrenergic receptor subtype
genes in mice has greatly enhanced our understanding of the
physiological functions and therapeutic potential of individual
2-receptor subtypes. 2-Adrenergic
receptors are important regulators of sympathetic tone,
neurotransmitter release, blood pressure, and intraocular pressure.
2-Receptor activation causes sedation and potent
analgesia. Further potential therapeutic functions may be unraveled
with the help of mouse models with deleted 2-receptor genes. Before these genetic animal models were available, it was hypothesized that each biological function of
2-receptors would be mediated by one receptor subtype.
Thus it was reasonable to assume that novel subtype-specific
pharmacological agonists or antagonists would be of great therapeutic
value because of their reduced potential for
2-receptor-mediated side effects. However, with more and
more studies of the 2-receptor physiology in
gene-targeted mice being published, the situation became more
complicated than initially anticipated. Indeed, only a few biological
functions of 2-receptors were found to be mediated by
one single 2-adrenergic receptor subtype. Examples are
the hypotension or sedation caused by 2A-receptor activation.
For other 2-receptor-mediated functions, two different
strategies seem to have emerged to regulate adrenergic signal
transduction: some biological functions are controlled by two
counteracting 2-receptor subtypes, e.g.,
2A-receptors decrease sympathetic outflow and blood
pressure, whereas the 2B-subtype increases blood
pressure by direct vasoconstriction. In contrast, the inhibitory presynaptic feedback loop that tightly regulates neurotransmitter release from adrenergic nerves requires two receptor subtypes, 2A and 2C, with similar but complementary
effects. Similarly, pain perception is controlled at several levels of
by one of the three 2-receptor subtypes.
The fact that more than one receptor subtype may be involved in
regulating one particular physiological function does not limit the
therapeutic potential of novel subtype-selective drugs for
2-adrenergic receptors. However, it emphasizes that
knowledge of the spectrum of in vivo biological effects is mandatory
before making precise predictions about the in vivo effects of
subtype-specific drugs. For treatment of hypertension, a selective
2A-receptor agonist without affinity for the
2B-receptor might be advantageous. As
2B-receptors counteract the hypotensive effect of
2A-receptor activation, a selective
2A-agonist could be given at a lower dose to achieve
similar blood pressure lowering with reduced sedative side effects. In
addition, a combination of agonistic and antagonistic properties may
become desirable, for instance, for antihypertensives, e.g.,
2A-agonist and 2B-antagonist. The primary
target for 2-mediated pain modulation would be the
2B-receptor. As illustrated by the potent analgesic
effect of nitrous oxide, 2B-receptor activation might be
a very promising analgesic strategy. Whether
2C-receptors are equally effective in inhibiting pain
pathways in the spinal cord has to be tested in future studies
(17). The main advantage of 2B- or
2C-receptor-specific agonists for antinociception would
be their lack of sedative side effects compared with nonselective 2-agonists that also stimulate
2A-receptors. In addition, they would not cause
respiratory depression and addiction, which are two major problems
associated with opioid therapy. In anesthesia and intensive care, the
availability of pairs of subtype-selective agonists and antagonists
might be of great benefit (66).
2A-Receptor-mediated sedation that can be rapidly
reversed by a selective 2-antagonist may be used in
future human anesthesia (as it is already being used with
non-subtype-selective agonists/antagonists in veterinary anesthesia).
Finally, mice lacking all 2-receptor subtypes will also
be essential tools to determine the function of imidazoline receptors
and the potential of future imidazoline receptor drugs (24,
51).
Further investigation of the specific function of
2-subtypes will greatly enhance our understanding of the
relevance of closely related receptor proteins and point out novel
therapeutic strategies for subtype-selective drug development.
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ACKNOWLEDGEMENTS |
Our work has been supported by the Deutsche Forschungsgemeinschaft.
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FOOTNOTES |
Address for reprint requests and other correspondence: L. Hein, Institut für Pharmakologie und Toxikologie,
Universität Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany
(hein{at}toxi.uni-wuerzburg.de).
10.1152/ajpregu.00123.2002
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REFERENCES |
1.
Adler, CH,
Meller E,
and
Goldstein M.
Receptor reserve at the 2 adrenergic receptor in the rat cerebral cortex.
J Pharmacol Exp Ther
240:
508-515,
1987[Abstract/Free Full Text].
2.
Altman, JD,
Trendelenburg AU,
MacMillan L,
Bernstein D,
Limbird L,
Starke K,
Kobilka BK,
and
Hein L.
Abnormal regulation of the sympathetic nervous system in 2A-adrenergic receptor knockout mice.
Mol Pharmacol
56:
154-161,
1999[Abstract/Free Full Text].
3.
Baumgart, D,
Haude M,
Gorge G,
Liu F,
Ge J,
Grosse-Eggebrecht C,
Erbel R,
and
Heusch G.
Augmented -adrenergic constriction of atherosclerotic human coronary arteries.
Circulation
99:
2090-2097,
1999[Abstract/Free Full Text].
4.
Bjorklund, M,
Sirvio J,
Puolivali J,
Sallinen J,
Jakala P,
Scheinin M,
Kobilka BK,
and
Riekkinen P, Jr.
2C-Adrenoceptor-overexpressing mice are impaired in executing nonspatial and spatial escape strategies.
Mol Pharmacol
54:
569-576,
1998[Abstract/Free Full Text].
5.
Bjorklund, M,
Sirvio J,
Riekkinen M,
Sallinen J,
Scheinin M,
and
Riekkinen P, Jr.
Overexpression of 2C-adrenoceptors impairs water maze navigation.
Neuroscience
95:
481-487,
2000[ISI][Medline].
6.
Bjorklund, M,
Sirvio J,
Sallinen J,
Scheinin M,
Kobilka BK,
and
Riekkinen P, Jr.
2C-Adrenoceptor overexpression disrupts execution of spatial and non-spatial search patterns.
Neuroscience
88:
1187-1198,
1999[ISI][Medline].
7.
Bjorklund, M,
Siverina I,
Heikkinen T,
Tanila H,
Sallinen J,
Scheinin M,
and
Riekkinen P, Jr.
Spatial working memory improvement by an 2-adrenoceptor agonist dexmedetomidine is not mediated through 2C-adrenoceptor.
Prog Neuropsychopharmacol Biol Psychiatry
25:
1539-1554,
2001[Medline].
8.
Brophy, JM,
Joseph L,
and
Rouleau JL.
-Blockers in congestive heart failure. A Bayesian meta-analysis.
Ann Intern Med
134:
550-560,
2001[Abstract/Free Full Text].
9.
Bücheler, M,
Hadamek K,
and
Hein L.
Two 2-adrenergic receptor subtypes, 2A and 2C, inhibit transmitter release in the brain of gene-targeted mice.
Neuroscience
109:
819-826,
2002[ISI][Medline].
10.
Bünemann, M,
Bücheler MM,
Philipp M,
Lohse MJ,
and
Hein L.
Activation and deactivation kinetics of 2A- and 2C- adrenergic receptor-activated G protein-activated inwardly rectifying K+ channel currents.
J Biol Chem
276:
47512-47517,
2001[Abstract/Free Full Text].
11.
Bylund, DB,
Eikenberg DC,
Hieble JP,
Langer SZ,
Lefkowitz RJ,
Minneman KP,
Molinoff PB,
Ruffolo RR,
and
Trendelenburg U.
International Union of Pharmacology nomenclature of adrenoceptors.
Pharmacol Rev
46:
121-136,
1994[ISI][Medline].
12.
Chotani, MA,
Flavahan S,
Mitra S,
Daunt D,
and
Flavahan NA.
Silent 2C-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries.
Am J Physiol Heart Circ Physiol
278:
H1075-H1083,
2000[Abstract/Free Full Text].
13.
Cussac, D,
Schaak S,
Denis C,
Flordellis C,
Calise D,
and
Paris H.
High level of 2-adrenoceptor in rat foetal liver and placenta is due to 2B-subtype expression in haematopoietic cells of the erythrocyte lineage.
Br J Pharmacol
133:
1387-1395,
2001[ISI][Medline].
14.
Daunt, DA,
Hurt C,
Hein L,
Kallio J,
Feng F,
and
Kobilka BK.
Subtype-specific intracellular trafficking of 2-adrenergic receptors.
Mol Pharmacol
51:
711-720,
1997[Abstract/Free Full Text].
15.
Docherty, JR.
Subtypes of functional 1- and 2-adrenoceptors.
Eur J Pharmacol
361:
1-15,
1998[ISI][Medline].
16.
Duka, I,
Gavras I,
Johns C,
Handy DE,
and
Gavras H.
Role of the postsynaptic 2-adrenergic receptor subtypes in catecholamine-induced vasoconstriction.
Gen Pharmacol
34:
101-106,
2000[ISI][Medline].
17.
Fairbanks, CA,
Stone LS,
Kitto KF,
Nguyen HO,
Posthumus IJ,
and
Wilcox GL.
2-Adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy.
J Pharmacol Exp Ther
300:
282-290,
2002[Abstract/Free Full Text].
18.
Fairbanks, CA,
and
Wilcox GL.
Moxonidine, a selective 2-adrenergic and imidazoline receptor agonist, produces spinal antinociception in mice.
J Pharmacol Exp Ther
290:
403-412,
1999[Abstract/Free Full Text].
19.
Freedman, RR,
Baer RP,
and
Mayes MD.
Blockade of vasospastic attacks by 2-adrenergic but not 1-adrenergic antagonists in idiopathic Raynaud's disease.
Circulation
92:
1448-1451,
1995[Abstract/Free Full Text].
20.
Frishman, WH,
and
Lazar EJ.
Reduction of mortality, sudden death and non-fatal reinfarction with -adrenergic blockers in survivors of acute myocardial infarction: a new hypothesis regarding the cardioprotective action of -adrenergic blockade.
Am J Cardiol
66:
66G-70G,
1990[Medline].
21.
Gavras, H,
and
Gavras I.
Salt-induced hypertension: the interactive role of vasopressin and of the sympathetic nervous system.
J Hypertens
7:
601-606,
1989[ISI][Medline].
22.
Gavras, I,
Manolis AJ,
and
Gavras H.
The 2-adrenergic receptors in hypertension and heart failure: experimental and clinical studies.
J Hypertens
19:
2115-2124,
2001[ISI][Medline].
23.
Guo, TZ,
Davies MF,
Kingery WS,
Patterson AJ,
Limbird LE,
and
Maze M.
Nitrous oxide produces antinociceptive response via 2B and/or 2C adrenoceptor subtypes in mice.
Anesthesiology
90:
470-476,
1999[ISI][Medline].
24.
Guyenet, PG.
Is the hypotensive effect of clonidine and related drugs due to imidazoline binding sites?
Am J Physiol Regulatory Integrative Comp Physiol
273:
R1580-R1584,
1997[Abstract/Free Full Text].
25.
Hein, L.
Transgenic models of 2-adrenergic receptor subtype function.
Rev Physiol Biochem Pharmacol
142:
161-185,
2001[ISI][Medline].
26.
Hein, L,
Altman JD,
and
Kobilka BK.
Two functionally distinct 2-adrenergic receptors regulate sympathetic neurotransmission.
Nature
402:
181-184,
1999[Medline].
27.
Hunter, JC,
Fontana DJ,
Hedley LR,
Jasper JR,
Lewis R,
Link RE,
Secchi R,
Sutton J,
and
Eglen RM.
Assessment of the role of 2-adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice.
Br J Pharmacol
122:
1339-1344,
1997[ISI][Medline].
28.
Janumpalli, S,
Butler LS,
MacMillan LB,
Limbird LE,
and
McNamara JO.
A point mutation (D79N) of the 2A adrenergic receptor abolishes the antiepileptogenic action of endogenous norepinephrine.
J Neurosci
18:
2004-2008,
1998[Abstract/Free Full Text].
29.
Jeyaraj, SC,
Chotani MA,
Mitra S,
Gregg HE,
Flavahan NA,
and
Morrison KJ.
Cooling evokes redistribution of 2C-adrenoceptors from Golgi to plasma membrane in transfected human embryonic kidney 293 cells.
Mol Pharmacol
60:
1195-1200,
2001[Abstract/Free Full Text].
30.
Kingery, WS,
Agashe GS,
Guo TZ,
Sawamura S,
Davies MF,
Clark JD,
Kobilka BK,
and
Maze M.
Isoflurane and nociception: spinal 2A adrenoceptors mediate antinociception while supraspinal 1 adrenoceptors mediate pronociception.
Anesthesiology
96:
367-374,
2002[ISI][Medline].
31.
Kintsurashvili, E,
Gavras I,
Johns C,
and
Gavras H.
Effects of antisense oligodeoxynucleotide targeting of the 2-adrenergic receptor messenger RNA in the central nervous system.
Hypertension
38:
1075-1080,
2001[Abstract/Free Full Text].
32.
Lakhlani, PP,
MacMillan LB,
Guo TZ,
McCool BA,
Lovinger DM,
Maze M,
and
Limbird LE.
Substitution of a mutant 2A-adrenergic receptor via "hit and run" gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo.
Proc Natl Acad Sci USA
94:
9950-9955,
1997[Abstract/Free Full Text].
33.
Lepor, H.
Long-term evaluation of tamsulosin in benign prostatic hyperplasia: placebo-controlled, double-blind extension of phase III trial. Tamsulosin Investigator Group.
Urology
51:
901-906,
1998[ISI][Medline].
34.
Link, RE,
Daunt D,
Barsh G,
Chruscinski A,
and
Kobilka BK.
Cloning of two mouse genes encoding 2-adrenergic receptor subtypes and identification of a single amino acid in the mouse 2-C10 homolog responsible for an interspecies variation in antagonist binding.
Mol Pharmacol
42:
16-27,
1992[Abstract].
35.
Link, RE,
Desai K,
Hein L,
Stevens ME,
Chruscinski A,
Bernstein D,
Barsh GS,
and
Kobilka BK.
Cardiovascular regulation in mice lacking 2-adrenergic receptor subtypes b and c.
Science
273:
803-805,
1996[Abstract].
36.
Link, RE,
Stevens MS,
Kulatunga M,
Scheinin M,
Barsh GS,
and
Kobilka BK.
Targeted inactivation of the gene encoding the mouse 2C-adreno
TOP
ABSTRACT
INTRODUCTION
2-ADRENERGIC RECEPTOR GENES
