Adrenergic Receptors
D B Bylund, University of Nebraska Medical Center, Omaha, NE, USA
ã 2013 Elsevier Inc. All rights reserved.
Glossary
Agonist Compound that binds to a receptor and activates it,
thus causing a biological response.
Antagonist Compound that binds to a receptor but does
not activate it. It can block or inhibit the activation caused by
an agonist.
Desensitization Decrease in response of a tissue to a
neurotransmitter or agonist drug following repeated
administration.
Adrenergic receptors (adrenoceptors) mediate the central and
peripheral actions of the neurotransmitter norepinephrine
(noradrenaline) and the hormone epinephrine (adrenaline);
they are widely distributed throughout the body. There are
three major adrenergic receptor types: alpha-1, alpha-2, and
beta. Each of these three receptor types is further divided into
three subtypes. Adrenergic receptors are seven transmembrane
receptors, which consist of a single polypeptide chain with
seven hydrophobic regions that form alpha helical structures
that span or transverse the membrane. Because the mechanism
of action of adrenergic receptors includes the activation of
guanine nucleotide regulatory binding proteins (G proteins),
they are also called G-protein-coupled receptors.
Epinephrine and Norepinephrine
Norepinephrine (noradrenaline) is a neurotransmitter in both
the peripheral and central nervous systems. Epinephrine
(adrenaline) is a hormone released from the adrenal gland.
Norepinephrine and epinephrine are catecholamines, because
they have both the catechol moiety (two hydroxyl groups on a
benzene ring) and an amine (NH2). Both of these catechol-
amine messengers play important roles in the regulation of
diverse physiological systems by acting through adrenergic
receptors. Stimulation of adrenergic receptors by catechola-
mines, released in response to activation of the sympathetic
autonomic nervous system, results in a variety of effects such as
increased heart rate, regulation of vascular tone, and broncho-
dilatation. In the central nervous system, adrenergic receptors
are involved in many functions, including memory, learning,
alertness, and the response to stress.
Norepinephrine is synthesized starting with the amino acid
tyrosine, which is obtained from the diet and can also be
synthesized from phenylalanine. Tyrosine is converted to dihy-
droxyphenylalanine (DOPA) by the enzyme tyrosine hydroxy-
lase, and DOPA in turn is converted to dopamine. Dopamine
is then converted to norepinephrine by the enzyme dopamine
beta-hydroxylase. In the adrenal medulla and in a few brain
Downregulation Decrease in the number or density
of receptor-binding sites following chronic agonist
treatment.
Partial agonist Agonist that has less than full efficacy in
activating its receptor.
Polymorphism Variability in DNA sequence that occurs
with an allele frequency of greater than 1% in the
population.
regions, norepinephrine is converted to epinephrine by the
enzyme phenylethanolamine N-methyltransferase. The major
mechanism by which the effects of norepinephrine are termi-
nated is reuptake back into the nerve terminal by a high-
affinity norepinephrine transporter. Epinephrine, as well as
norepinephrine, are metabolized to inactive products. Nor-
epinephrine is metabolized by the enzymes monoamine oxi-
dase (MAO) and catechol-O-methyltransferase (COMT) to
3-methoxy-4-hydroxyphenylglycol (MHPG) and 3-methoxy-
4-hydroxymandelic acid (VMA). The major metabolite found
in the blood and urine is MHPG. Epinephrine is similarly
metabolized by MAO and COMT to VMA.
Classification and Mechanism of Action of
Adrenergic Receptors
Adrenergic receptors were originally divided into two major
types, alpha and beta, based on their pharmacological charac-
teristics (i.e., rank order potency of agonists). Subsequently,
the beta adrenergic receptors were subdivided into beta-1 and
beta-2 subtypes; more recently, a beta-3 subtype has been
defined. The alpha adrenergic receptors were first subdivided
into postsynaptic (alpha-1) and presynaptic (alpha-2) sub-
types. After it was realized that not all alpha receptors with
alpha-2 pharmacological characteristics were presynaptic, the
pharmacological definition was used. The current classification
scheme is based on three major types: alpha-1, alpha-2, and
beta. Each of these three receptor types is further divided into
three subtypes as shown in Figure 1: alpha-1A, alpha-1B,
alpha-1D; alpha-2A, alpha-2B, alpha-2 C; and beta-1, beta-2,
beta-3.
The binding of an agonist to an adrenergic receptor induces
(or stabilizes) a conformational change that allows the recep-
tor to interact with and activate a G protein. The activated
receptor facilitates the exchange of guanidine diphosphate for
guanidine triphosphate, leading to the dissociation of the a
and bg subunits of the G protein, which in turn stimulate or
inhibit the activity of various effectors. It is important to note
57
58 Signaling | Adrenergic Receptors
Adrenergic receptors
Alpha-1 Alpha-2 Beta
Alpha-1A Alpha-1B Alpha-1D Beta-1 Beta-2 Beta-3
Alpha-2A Alpha-2B Alpha-2C
Figure 1 The classification scheme for adrenergic receptors.
that each of the three types of adrenergic receptors couples to a
distinct class of G proteins: alpha-1 to Gq; alpha-2 to Gi/o; and
beta to Gs. In addition to G proteins, adrenergic receptors
interact with other signaling proteins and pathways such as
those involving tyrosine kinases.
Alpha-1 Adrenergic Receptors
Three genetic and four pharmacological alpha-1 adrenergic
receptor subtypes have been defined. The alpha-1A and
alpha-1B subtypes were initially defined based on their differ-
ential affinity for adrenergic agents, such as WB4101 and
phentolamine, and on their differential sensitivities to the
site-directed alkylating agent chloroethylclonidine. The alpha-
1B subtype was subsequently cloned from the hamster and the
alpha-1A was cloned from bovine brain, although it was origi-
nally called the alpha-1c adrenergic receptor. A third subtype,
the alpha-1D adrenergic receptor, was subsequently cloned
from the rat cerebral cortex, although this clone was originally
called the alpha-1a subtype by some investigators. A fourth
pharmacological subtype, the alpha-1L, has been identified
in vascular tissues from several species, but it may represent a
conformational state of the alpha-1A receptor. The current
classification scheme includes the alpha-1A, the alpha-1B,
and the alpha-1D, but there is no alpha-1 C (Figure 1).
Pharmacological and Molecular Characteristics of
Alpha-1 Adrenergic Receptors
In addition to norepinephrine and epinephrine, alpha-1 recep-
tors are activated by various agonists such as phenylephrine
(neosynephrine) and methoxamine (Vasoxyl). These agonists
are relatively selective for alpha-1 receptors and have low affin-
ity for alpha-2 and beta receptors. By contrast, they have simi-
lar affinities for the three alpha-1 subtypes and are thus
nonsubtype selectively agonists. Similarly, antagonists includ-
ing prazosin (Minipress) and tamsulosin (Flomax) are rela-
tively selective for alpha-1 receptors and block alpha-2 and
beta receptors only at high concentrations. Several other
antagonists such as phentolamine (Regitine) and phenoxy-
benzamine (Dibenzyline) block both alpha-1 and alpha-2
adrenergic receptors with similar affinities. Alpha-1A selective
antagonists include 5-methylurapidil and niguldipine, whereas
cirazoline appears to be a selective alpha-1A agonist.
The alpha-1 adrenergic receptors are single polypeptide
chains of 446–572 amino acid residues that span the membrane
7 times, with the amino terminal being extracellular and the
carboxy terminal intracellular. Thus, there are three intracellular
loops and three extracellular loops. In contrast to the alpha-
2 receptors, but similar to the beta receptors, the alpha-1 recep-
tors have a long carboxy terminal tail (137–179 amino acid
residues) and a short third intracellular loop (68–73 amino
acid residues). The amino terminal of the alpha-1A and alpha-
1B subtypes have three (alpha-1A) or four (alpha-1B) consensus
sites for N-linked glycosylation. The carboxy terminal tails of all
three subtypes are potentially palmitolyated, thus anchoring the
tail to the membrane and forming a small fourth intracellular
loop. The carboxy terminal tails also have multiple sites of
phosphorylation that are thought to be important in the desen-
sitization, recycling, and downregulation of the receptor.
The human alpha-1 adrenergic receptor genes consist of
two exons and a single large intron of at least 20 kb in the
region corresponding to the sixth transmembrane domain. No
splice variants are known for the alpha-1B and alpha-1D sub-
types. By contrast, at least 10 splice variants of human alpha-1A
subtype have been reported, but only four produce full-length
receptors.
Alpha-2 Adrenergic Receptors
Three genetic and four pharmacological alpha-2 adrenergic
receptor subtypes have also been defined (Figure 1). The
alpha-2A and alpha-2B subtypes were initially defined based
on their differential affinity for adrenergic agents such as pra-
zosin and oxymetazoline. These subtypes were subsequently
cloned from human, rat, and mouse. A third subtype, alpha-
2 C, was originally identified in an opossum kidney cell line
and has also been cloned from several species. A fourth phar-
macological subtype, the alpha-2D, has been identified in the
rat, mouse, and cow. This pharmacological subtype is a species
ortholog of the human alpha-2A subtype, and thus it is not a
separate genetic subtype.
Pharmacological and Molecular Characteristics of
Alpha-2 Adrenergic Receptors
In addition to norepinephrine and epinephrine, alpha-2
receptors are activated by clonidine (Catapres) and brimoni-
dine (Alphagan). These agonists are relatively selective for
alpha-2 receptors and have lower affinity at alpha-1 and beta
receptors. Similarly, the antagonist yohimibine is relatively
selective for alpha-2 receptors and blocks alpha-1 and beta
receptors only at higher concentrations. Antagonists that are
at least somewhat selective for one of the alpha-2 subtypes
include BRL44408 for the alpha-2A, prazosin and ARC-239
for the alpha-2B (note, however, that these two agents have
much higher affinities for alpha-1 receptors), and rauwolscine
for the alpha-2 C subtype. Ozymetazoline is a partial agonist
that has a higher affinity for the alpha-2A subtype when
compared to the alpha-2B and alpha-2 C subtypes.

The alpha-2 adrenergic receptors are single polypeptide
chains of 450–462 amino acid residues. In contrast to the
alpha-1 and beta receptors, the alpha-2 receptors tend to have
long third intracellular loops (148–179 amino acid residues)
and a short carboxy terminal tail (20–21 amino acid residues).
The amino terminal of the alpha-2A and alpha-2 C subtypes
has two consensus sites for N-linked glycosylation, and the
carboxy terminal tails of all three subtypes are potentially
palmitolyated. The third intracellular loops have multiple
sites of phosphorylation, which are thought to be important
in the desensitization, recycling, and downregulation of the
receptor. The alpha-2 adrenergic receptor genes do not contain
introns, and thus there are no splice variants.
Beta Adrenergic Receptors
Three beta adrenergic receptor subtypes have been identified.
The beta-1 adrenergic receptor, the dominant receptor in heart
and adipose tissue, is equally sensitive to epinephrine and
norepinephrine, whereas the beta-2 adrenergic receptor, re-
sponsible for relaxation of vascular, uterine, and airway
smooth muscle, is less sensitive to norepinephrine as com-
pared to epinephrine. The beta-3 receptor is insensitive to the
commonly used beta-adrenergic receptor antagonists and was
previously referred to as the ‘atypical’ beta adrenergic receptor.
A beta-4 receptor has been postulated; however, definitive
evidence of its existence is lacking, and it is now thought to
be a ‘state’ of the beta-1 adrenergic receptor.
Pharmacological and Molecular Characteristics of
Beta Adrenergic Receptors
Isoproterenol (Isuprel) is the prototypic nonsubtype selective
beta agonist that has no activity at alpha-1 and alpha-2 recep-
tors except at high concentrations. Epinephrine is 10–100-fold
more potent at the beta-2 receptor as compared to the beta-1
subtype, whereas norepinephrine is more potent than epi-
nephrine at the beta-3 subtype. Many beta-2 selective agonists,
such as terbutaline (Brethine) and salmeterol (Serevent), have
been developed for the treatment of asthma. Due to their
subtype selectivity, they have a lower incidence of side effects
mediated by the beta-1 receptor. Propranolol (Inderal) is the
prototypic nonsubtype selective beta antagonist that has equal
affinities at the beta-1 and beta-2 subtypes. Other nonselective
beta adrenergic antagonists include timolol (Blocadren), pin-
dolol (Visken, which is actually a weak partial agonist), and
carvedilol (Coreg), which is also an alpha-1 antagonist. Several
beta-1 selective antagonists have been developed, such as met-
oprolol (Lopressor) and esmolol (Brevibloc).
The beta adrenergic receptors are single polypeptide chains
of 408–477. In contrast to the alpha-2 receptors, but similar to
the alpha-1 receptors, the beta receptors tend to have longer
carboxy terminal tails (61–97 amino acid residues) and shorter
third intracellular loops (54–80 amino acids). The amino ter-
minal of the beta receptors have one or two consensus sites for
N-linked glycosylation, and the carboxy terminal tails are
potentially palmitoylated. The carboxy terminal tails also
have multiple sites of phosphorylation, which are thought to
Signaling | Adrenergic Receptors 59
be important in the desensitization, recycling, and downregu-
lation of the receptor. The crystal structure of modified beta-
2 adrenergic receptors has been determined.
The beta-1 and beta-2 adrenergic receptor genes do not
contain introns; thus, they have no splice variants. By contrast,
the beta-3 receptor has one intron, resulting in two splice
variants. However, no functional differences have been found
between the two splice variants.
Regulation of Adrenergic Receptors
The processes involved in homologous desensitization and
downregulation have been extensively investigated for the
beta-2 adrenergic receptor. The other adrenergic receptors, as
well as many other G-protein-coupled receptors, appear to
behave in a similar manner. Initial uncoupling of the beta-
2 receptor from the G protein after agonist binding is mediated
by phosphorylation of specific residues in the carboxyl tail of
the receptor. The phosphorylated beta-2 receptor serves as a
substrate for the binding of b-arrestin, which not only uncou-
ples the receptor from the signal transduction process but also
serves as an adapter protein that mediates the binding of
additional signaling proteins and entry into the internalization
pathway. The mechanisms of beta-2 adrenergic receptor down-
regulation appear to involve both an increase in the rate of
degradation of the receptor as well as a decrease in the levels
of beta receptor messenger RNA (mRNA).
Adrenergic Receptor Signal Transduction Pathways
The alpha-1 adrenergic receptors activate the Gq/11 family of G
proteins leading to the dissociation of the a and bg subunits
and the subsequent stimulation of the enzyme phospholipase C.
This enzyme hydrolyzes phosphatidylinositol 1,2-biphosphate
in the membrane producing inositol trisphosphate (IP3) and
diacylglycerol. These molecules act as second messengers
mediating intracellular Ca2þ release via the IP3 receptor and
activating protein kinase C. Other signaling pathways that have
also been shown to be activated by alpha-1 receptors include
Ca2þ influx via voltage-dependent and -independent calcium
channels, arachidonic acid release, and activation of phospho-
lipase A2, phospholipase D, and mitogen-activated protein
kinase.
The alpha-2 adrenergic receptors activate the Gi/o family of G
proteins and alter (classically inhibit) the activity of the enzyme
adenylyl cyclase, which, in turn, decreases the concentration of
the second messenger cyclic adenosine monophosphate (AMP).
In addition, the stimulation of alpha-2 receptors can regulate
several other effector systems including the activation of Kþ
channels, inhibition or activation of Ca2þ channels, and activa-
tion of phospholipase A2, phospholipase C, and Naþ/Hþ
exchange.
The beta adrenergic receptors activate the Gs family of G
proteins and activate adenylyl cyclase, thus increasing cyclic
AMP concentrations. Beta adrenergic receptors interact with
many other signaling proteins, including the phosphoprotein
EBP50 (ezrin–radixin–moesin-binding phosphoprotein-50),
the Naþ/Hþ exchanger regulatory factor, and with CNrasGEF.
60 Signaling | Adrenergic Receptors
Adrenergic Receptor Polymorphisms
Polymorphisms have been identified in some of the alpha-
2 and beta adrenergic receptor subtypes, which may have
important clinical implications. A common polymorphism
has been identified in the third intracellular loop of the
alpha-2B receptor, which consists of a deletion of three gluta-
mate residues (301–303) that results in a loss of short-term
agonist-induced desensitization. This deletion is a risk factor
for acute coronary events, but not hypertension. A common
polymorphism has been identified in the third intracellular
loop of alpha-2 C subtype, which consists of a deletion of
four amino acid residues (322–325).
The gene encoding the human beta-1 adrenergic receptor is
quite polymorphic with 18 single-nucleotide polymorphisms,
7 of which cause amino acid substitutions. A total of 13 poly-
morphisms in the beta-2 adrenergic receptor gene and its tran-
scriptional regulator upstream peptide has been identified.
Three closely linked polymorphisms, two coding regions at
amino acid positions 16 and 27 and one in the upstream
peptide, are common in the general Caucasian population.
The glycine-16 receptor exhibits enhanced downregulation
in vitro after agonist exposure. By contrast, arginine-16 recep-
tors are more resistant to downregulation. Some studies have
suggested a relationship among these polymorphisms, airway
responsiveness (e.g., asthma), and the responsiveness to beta
adrenergic agonists.
A tryptophan-64 to arginine polymorphism has been iden-
tified in the beta-3 adrenergic receptor. The allele frequency is
approximately 30% in the Japanese population, higher in Pima
Indians, and lower in Caucasians. Type 2 diabetic patients with
this mutation showed a significantly younger onset age of
diabetes and an increased tendency to obesity, hyperinsuline-
mia, and hypertension.
See also: Metabolism Vitamins and Hormones: Diabetes;
Signaling: Adenylyl Cyclases; Dopamine Receptors; G-Protein-
Coupled Receptor Kinases and Arrestins; Inositol Phosphate Kinases
and Phosphatases; Phosphatidylinositol Bisphosphate and
Trisphosphate; Phospholipase C; Phospholipase D.
Further Reading
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biological evidence converge. Trends in Pharmacological Sciences 9: 356–361.
Bylund DB, Eikenberg DC, Hieble JP, et al. (1994) International Union of Pharmacology
nomenclature of adrenoceptors. Pharmacological Reviews 46: 121–136.
Cooper JR, Bloom FE, and Roth RH (2003) The Biochemical Basis of
Neuropharmacology, 8th edn. New York, NY: Oxford University Press.
Crassous PA, Denis C, Paris H, and Senard JM (2007) Interest of alpha2-adrenergic
agonists and antagonists in clinical practice: Background, facts and perspectives.
Current Topics in Medicinal Chemistry 7: 187–194.
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Molecular Life Sciences 67: 405–417.
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subtypes-mediated physiological, pharmacological actions. Neurochemistry
International 55: 447–453.
Hein P and Michel MC (2007) Signal transduction and regulation: Are all
alpha1-adrenergic receptor subtypes created equal? Biochemical Pharmacology
73: 1097–1106.
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models. Neurochemistry International 51: 277–281.
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heart failure. Heart Failure Clinics 6: 27–33.
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Rosenbaum DM, Rasmussen SG, and Kobilka BK (2009) The structure and function
of G protein-coupled receptors. Nature 459: 356–363.