The beta-2 adrenergic receptor (β
2 adrenoreceptor), also known as ADRB2, is a cell membrane-spanning
beta-adrenergic receptor that
binds epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
(adrenaline), a hormone and
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neu ...
whose signaling, via
adenylate cyclase stimulation through trimeric Gs proteins, increased
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
, and downstream
L-type calcium channel
The L-type calcium channel (also known as the dihydropyridine channel, or DHP channel) is part of the high-voltage activated family of voltage-dependent calcium channel.
"L" stands for long-lasting referring to the length of activation. This ...
interaction, mediates physiologic responses such as
smooth muscle
Smooth muscle is an involuntary non- striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit ...
relaxation and bronchodilation.
Robert J.Lefkowitz and Brian Kobilka studied beta 2 adrenergic receptor as a model system which rewarded them the 2012 Nobel Prize in Chemistry “for groundbreaking discoveries that reveal the inner workings of an important family of such receptors: G-protein-coupled-receptors”.
The official symbol for the human
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
encoding the β
2 adrenoreceptor is ''ADRB2''.
Gene
The gene is
intron
An intron is any Nucleic acid sequence, nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of ...
less. Different polymorphic forms,
point mutations, and/or
downregulation
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pr ...
of this gene are associated with nocturnal
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...
,
obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
and
type 2 diabetes
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinatio ...
.
Structure
The 3D crystallographic structure (see figure and links to the right) of the β
2-adrenergic receptor has been determined
by making a
fusion protein
Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this '' fusion gene'' ...
with
lysozyme to increase the hydrophilic surface area of the protein for crystal contacts. An alternative method, involving production of a fusion protein with an agonist, supported lipid-bilayer co-crystallization and generation of a 3.5 Å resolution structure.
The Crystal Structure of the β2Adrenergic Receptor-Gs protein complex was solved in 2011. The largest conformational changes in the β2AR include a 14 Å outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an alpha helical extension of the cytoplasmic end of TM5.
Mechanism
This receptor is directly associated with one of its ultimate effectors, the class C
L-type calcium channel
The L-type calcium channel (also known as the dihydropyridine channel, or DHP channel) is part of the high-voltage activated family of voltage-dependent calcium channel.
"L" stands for long-lasting referring to the length of activation. This ...
Ca
V1.2. This receptor-channel complex is
coupled
''Coupled'' is an American dating game show that aired on Fox from May 17 to August 2, 2016. It was hosted by television personality, Terrence J and created by Mark Burnett, of '' Survivor'', ''The Apprentice'', '' Are You Smarter Than a 5th G ...
to the
Gs G protein
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their a ...
, which activates
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
, catalysing the formation of
cyclic adenosine monophosphate (cAMP) which then activates
protein kinase A, and counterbalancing
phosphatase
In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid monoester into a phosphate ion and an alcohol. Because a phosphatase enzyme catalyzes the hydrolysis of its substrate, it is a subcategory of hydrolase ...
PP2A. Protein kinase A then goes on to phosphorylate (and thus inactivate)
myosin light-chain kinase
Myosin light-chain kinase also known as MYLK or MLCK is a serine/threonine-specific protein kinase that phosphorylates a specific myosin light chain, namely, the regulatory light chain of myosin II.
General structural features
While there ar ...
, which causes smooth muscle relaxation, accounting for the vasodilatory effects of beta 2 stimulation. The assembly of the signaling complex provides a mechanism that ensures specific and rapid signaling. A two-state biophysical and molecular model has been proposed to account for the pH and REDOX sensitivity of this and other GPCRs.
Beta-2 adrenergic receptors have also been found to couple with
Gi, possibly providing a mechanism by which response to ligand is highly localized within cells. In contrast, Beta-1 adrenergic receptors are coupled only to G
s, and stimulation of these results in a more diffuse cellular response.
This appears to be mediated by cAMP induced PKA phosphorylation of the receptor.
Interestingly, Beta-2 adrenergic receptor was observed to localize exclusively to the T-tubular network of adult cardiomyocytes, as opposed to Beta-1 adrenergic receptor, which is observed also on the outer plasma membrane of the cell
Function
Musculoskeletal system
Activation of the β
2 adrenoreceptor with long-acting agents such as oral
clenbuterol and intravenously-infused
albuterol results in skeletomuscular hypertrophy and anabolism. The comprehensive anabolic, lipolytic, and ergogenic effects of long-acting β
2 agonists such as clenbuterol render them frequent targets as performance-enhancing drugs in athletes. Consequently, such agents are monitored for and generally banned by WADA (World Anti-Doping Agency) with limited permissible usage under therapeutic exemptions; clenbuterol and other β
2 adrenergic agents remain banned not as a beta-agonist, but rather an anabolic agent. These effects are largely attractive within agricultural contexts insofar that β
2 adrenergic agents have seen notable extra-label usage in food-producing animals and livestock. While many countries including the United States have prohibited extra-label usage in food-producing livestock, the practice is still observed in many countries.
Circulatory system
* Heart muscle contraction
* Increase
cardiac output
In cardiac physiology, cardiac output (CO), also known as heart output and often denoted by the symbols Q, \dot Q, or \dot Q_ , edited by Catherine E. Williamson, Phillip Bennett is the volumetric flow rate of the heart's pumping output: th ...
(minor degree compared to β
1).
**Increases
heart rate[ in sinoatrial node (SA node) ( chronotropic effect).
**Increases atrial ]cardiac muscle
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle ...
contractility. (inotropic
An inotrope is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction.
The term ''inotro ...
effect).
**Increases contractility and automaticity[ of ventricular cardiac muscle.
*Dilate hepatic artery.
*Dilate ]arterioles
An arteriole is a small-diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillaries.
Arterioles have muscular walls (usually only one to two layers of smooth muscle cells) and are the pri ...
to skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of m ...
.
Eye
In the normal eye, beta-2 stimulation by salbutamol
Salbutamol, also known as albuterol and sold under the brand name Ventolin among others, is a medication that opens up the medium and large airways in the lungs. It is a short-acting β2 adrenergic receptor agonist which works by causing rel ...
increases intraocular pressure via net:
* Increase in production of aqueous humour
The aqueous humour is a transparent water-like fluid similar to plasma, but containing low protein concentrations. It is secreted from the ciliary body, a structure supporting the lens of the eyeball. It fills both the anterior and the posteri ...
by the ciliary process,
* Subsequent increased pressure-dependent uveoscleral outflow of humour, ''despite'' reduced drainage of humour via the Canal of Schlemm.
In glaucoma
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for aqueous humor, fluid withi ...
, drainage is reduced (open-angle glaucoma) or blocked completely (closed-angle glaucoma). In such cases, beta-2 stimulation with its consequent increase in humour production is highly contra-indicated, and conversely, a topical beta-2 antagonist such as timolol may be employed.
Digestive system
* Glycogenolysis
Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.
Mechanism
T ...
and gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non- carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verteb ...
in liver.[
* ]Glycogenolysis
Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.
Mechanism
T ...
and lactate
Lactate may refer to:
* Lactation, the secretion of milk from the mammary glands
* Lactate, the conjugate base of lactic acid
Lactic acid is an organic acid. It has a molecular formula . It is white in the solid state and it is miscible with w ...
release in skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of m ...
.[
* Contract ]sphincters
A sphincter is a circular muscle that normally maintains constriction of a natural body passage or orifice and which relaxes as required by normal physiological functioning. Sphincters are found in many animals. There are over 60 types in the hum ...
of Gastrointestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
.
* Thickened secretions from salivary gland
The salivary glands in mammals are exocrine glands that produce saliva through a system of ducts. Humans have three paired major salivary glands ( parotid, submandibular, and sublingual), as well as hundreds of minor salivary glands. Salivary ...
s.[
*]Insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism ...
and glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a medication to tre ...
secretion from pancreas.
Other
* Inhibit histamine
Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discover ...
-release from mast cells
A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a p ...
.
* Increase protein content of secretions from lacrimal gland
The lacrimal glands are paired exocrine glands, one for each eye, found in most terrestrial vertebrates and some marine mammals, that secrete the aqueous layer of the tear film. In humans, they are situated in the upper lateral region of each or ...
s.
* Receptor also present in cerebellum
The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebe ...
.
* Bronchiole dilation (targeted while treating asthma attacks)
* Involved in brain - immune - communication
Ligands
Agonists
Spasmolytics used in
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...
and COPD
Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...
* Short-acting β2 agonists (SABA)
** bitolterol
Bitolterol mesylate (Tornalate) is a short-acting β2 adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and COPD. In these disorders there is a narrowing of the airways (bronchi and their ramifications ...
** fenoterol
** hexoprenaline
** isoprenaline ( INN) or isoproterenol ( USAN)
** levosalbutamol ( INN) or levalbuterol ( USAN)
** orciprenaline ( INN) or metaproterenol ( USAN)
** pirbuterol
** procaterol
Procaterol is an intermediate-acting β2 adrenoreceptor agonist used for the treatment of asthma. It has never been filed for FDA evaluation in the United States, where it is not marketed. The drug is readily oxidized in the presence of moisture ...
** salbutamol
Salbutamol, also known as albuterol and sold under the brand name Ventolin among others, is a medication that opens up the medium and large airways in the lungs. It is a short-acting β2 adrenergic receptor agonist which works by causing rel ...
( INN) or albuterol ( USAN)
** terbutaline
* Long-acting β2 agonists (LABA)
** arformoterol (some consider it to be an ultra-LABA)
** bambuterol
** clenbuterol
** formoterol
** salmeterol
* Ultra-long-acting β2 agonists (ultra-LABA)
** carmoterol
** indacaterol
Indacaterol is an ultra-long-acting beta-adrenoceptor agonist developed by Novartis. It needs to be taken only once a day, unlike the related drugs formoterol and salmeterol. It is licensed only for the treatment of chronic obstructive pulmonar ...
** milveterol (GSK 159797)
** olodaterol
Olodaterol (trade name Striverdi Respimat) is an ultra- long-acting β adrenoreceptor agonist (ultra-LABA) used as an inhalation for treating people with chronic obstructive pulmonary disease (COPD). It is manufactured by Boehringer Ingelheim.Stri ...
** vilanterol (GSK 642444)
Tocolytic agents
* Short-acting β2 agonists (SABA)
** fenoterol
** hexoprenaline
** isoxsuprine
** ritodrine
** salbutamol
Salbutamol, also known as albuterol and sold under the brand name Ventolin among others, is a medication that opens up the medium and large airways in the lungs. It is a short-acting β2 adrenergic receptor agonist which works by causing rel ...
( INN) or albuterol ( USAN)
** terbutaline
β2 agonists used for other purposes
* zilpaterol
Antagonists
''(Beta blocker
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack after a first heart attack ( secondary prevention). They are ...
s)''
* butoxamine*[
* First generation (non-selective) β-blockers
* ICI-118,551*
* Propranolol
* denotes selective antagonist to the receptor.
]
Allosteric modulators
* compound-6FA, PAM at intracellular binding site
Interactions
Beta-2 adrenergic receptor has been shown to interact
Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...
with:
* AKAP12
A-kinase anchor protein 12, aka AKAP250, is an enzyme that in humans is encoded by the ''AKAP12'' gene.
Function
The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to t ...
,
* OPRD1,
* Grb2,
* SNX27 and
* SLC9A3R1
Sodium-hydrogen antiporter 3 regulator 1 is a regulator of Sodium-hydrogen antiporter 3. It is encoded by the gene ''SLC9A3R1''. It is also known as ERM Binding Protein 50 (EBP50) or Na+/H+ Exchanger Regulatory Factor (NHERF1). It is believed t ...
.
See also
*Other adrenergic receptors
The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like bet ...
** Alpha-1 adrenergic receptor
** Alpha-2 adrenergic receptor
** Beta-1 adrenergic receptor
** Beta-3 adrenergic receptor
* Discovery and development of beta2 agonists
β2-adrenoceptor agonists is a group of drugs that act selectively on β2-receptors in the lungs causing bronchodilation. β2-agonists are used to treat asthma and COPD, diseases that cause obstruction in the airways. Prior to their discovery, the ...
References
Further reading
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External links
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{{G protein-coupled receptors, g1
Adrenergic receptors