The beta-2 adrenergic receptor (β2 adrenoreceptor), also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor that binds epinephrine (adrenaline), a hormone and neurotransmitter whose signaling, via adenylate cyclase stimulation through trimeric Gs proteins, increases cAMP, and, via downstream L-type calcium channel interaction, mediates physiologic responses such as smooth muscle relaxation and bronchodilation. [5]
Robert J. Lefkowitz [6] and Brian Kobilka [7] studied beta 2 adrenergic receptor as a model system which rewarded them the 2012 Nobel Prize in Chemistry [8] “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 encoding the β2 adrenoreceptor is ADRB2. [9]
The ADRB2 gene is intronless. Different polymorphic forms, point mutations, and/or downregulation of this gene are associated with nocturnal asthma, obesity and type 2 diabetes. [10]
The 3D crystallographic structure (see figure and links to the right) of the β2-adrenergic receptor has been determined [11] [12] [13] by making a fusion protein 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. [14]
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. [15]
This receptor is directly associated with one of its ultimate effectors, the class C L-type calcium channel CaV1.2.[ citation needed] This receptor-channel complex is coupled to the Gs G protein, which activates adenylyl cyclase, catalysing the formation of cyclic adenosine monophosphate (cAMP) which then activates protein kinase A, and counterbalancing phosphatase PP2A. Protein kinase A then goes on to phosphorylate (and thus inactivate) myosin light-chain kinase, 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. [16]
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 Gs, and stimulation of these results in a more diffuse cellular response. [17] This appears to be mediated by cAMP induced PKA phosphorylation of the receptor. [18] 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 [19]
Function | Tissue | Biological Role |
---|---|---|
Smooth muscle relaxation in: | GI tract (decreases motility) | Inhibition of digestion |
Bronchi [20] | Facilitation of respiration. | |
Detrusor urinae muscle of bladder wall [21] [22] This effect is stronger than the alpha-1 receptor effect of contraction. | Inhibition of need for micturition | |
Uterus | Inhibition of labor | |
Seminal tract [23] | ||
Increased perfusion and vasodilation | Blood vessels and arteries to skeletal muscle including the smaller coronary arteries [24] and hepatic artery | Facilitation of muscle contraction and motility |
Increased mass and contraction speed | Striated muscle [23] | |
Insulin and glucagon secretion | Pancreas [25] | Increased blood glucose and uptake by skeletal muscle |
Glycogenolysis [23] | ||
Tremor | Motor nerve terminals. [23] Tremor is mediated by PKA mediated facilitation of presynaptic Ca2+ influx leading to acetylcholine release. |
Legend
The function facilitates the
fight-or-flight response.
|
Activation of the β2 adrenoreceptor with long-acting agents such as oral clenbuterol and intravenously-infused albuterol results in skeletomuscular hypertrophy and anabolism. [26] [27] The comprehensive anabolic, lipolytic, and ergogenic effects of long-acting β2 agonists such as clenbuterol render them frequent targets as performance-enhancing drugs in athletes. [28] 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 β2 adrenergic agents remain banned not as a beta-agonist, but rather an anabolic agent. These effects are largely attractive within agricultural contexts insofar that β2 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. [29] [30]
In the normal eye, beta-2 stimulation by salbutamol increases intraocular pressure via net:
In glaucoma, 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.
Beta-2 adrenergic receptor | |
---|---|
Transduction mechanisms | Primary:
Gs Secondary: Gi/o |
Primary endogenous agonists | epinephrine, norepinephrine |
Agonists | isoprenaline, salbutamol, salmeterol, others |
Antagonists | carvedilol, propranolol, labetalol, others |
Inverse agonists | N/A |
Positive allosteric modulators | Zn2+ (low concentrations) |
Negative allosteric modulators | Zn2+ (high concentrations) |
External resources | |
IUPHAR/BPS | 29 |
DrugBank | P07550 |
HMDB | HMDBP01634 |
* denotes selective antagonist to the receptor.
Beta-2 adrenergic receptor has been shown to interact with:
ADRB2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
Aliases | ADRB2, ADRB2R, ADRBR, B2AR, BAR, BETA2AR, adrenoceptor beta 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 109690; MGI: 87938; HomoloGene: 30948; GeneCards: ADRB2; OMA: ADRB2 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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The beta-2 adrenergic receptor (β2 adrenoreceptor), also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor that binds epinephrine (adrenaline), a hormone and neurotransmitter whose signaling, via adenylate cyclase stimulation through trimeric Gs proteins, increases cAMP, and, via downstream L-type calcium channel interaction, mediates physiologic responses such as smooth muscle relaxation and bronchodilation. [5]
Robert J. Lefkowitz [6] and Brian Kobilka [7] studied beta 2 adrenergic receptor as a model system which rewarded them the 2012 Nobel Prize in Chemistry [8] “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 encoding the β2 adrenoreceptor is ADRB2. [9]
The ADRB2 gene is intronless. Different polymorphic forms, point mutations, and/or downregulation of this gene are associated with nocturnal asthma, obesity and type 2 diabetes. [10]
The 3D crystallographic structure (see figure and links to the right) of the β2-adrenergic receptor has been determined [11] [12] [13] by making a fusion protein 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. [14]
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. [15]
This receptor is directly associated with one of its ultimate effectors, the class C L-type calcium channel CaV1.2.[ citation needed] This receptor-channel complex is coupled to the Gs G protein, which activates adenylyl cyclase, catalysing the formation of cyclic adenosine monophosphate (cAMP) which then activates protein kinase A, and counterbalancing phosphatase PP2A. Protein kinase A then goes on to phosphorylate (and thus inactivate) myosin light-chain kinase, 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. [16]
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 Gs, and stimulation of these results in a more diffuse cellular response. [17] This appears to be mediated by cAMP induced PKA phosphorylation of the receptor. [18] 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 [19]
Function | Tissue | Biological Role |
---|---|---|
Smooth muscle relaxation in: | GI tract (decreases motility) | Inhibition of digestion |
Bronchi [20] | Facilitation of respiration. | |
Detrusor urinae muscle of bladder wall [21] [22] This effect is stronger than the alpha-1 receptor effect of contraction. | Inhibition of need for micturition | |
Uterus | Inhibition of labor | |
Seminal tract [23] | ||
Increased perfusion and vasodilation | Blood vessels and arteries to skeletal muscle including the smaller coronary arteries [24] and hepatic artery | Facilitation of muscle contraction and motility |
Increased mass and contraction speed | Striated muscle [23] | |
Insulin and glucagon secretion | Pancreas [25] | Increased blood glucose and uptake by skeletal muscle |
Glycogenolysis [23] | ||
Tremor | Motor nerve terminals. [23] Tremor is mediated by PKA mediated facilitation of presynaptic Ca2+ influx leading to acetylcholine release. |
Legend
The function facilitates the
fight-or-flight response.
|
Activation of the β2 adrenoreceptor with long-acting agents such as oral clenbuterol and intravenously-infused albuterol results in skeletomuscular hypertrophy and anabolism. [26] [27] The comprehensive anabolic, lipolytic, and ergogenic effects of long-acting β2 agonists such as clenbuterol render them frequent targets as performance-enhancing drugs in athletes. [28] 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 β2 adrenergic agents remain banned not as a beta-agonist, but rather an anabolic agent. These effects are largely attractive within agricultural contexts insofar that β2 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. [29] [30]
In the normal eye, beta-2 stimulation by salbutamol increases intraocular pressure via net:
In glaucoma, 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.
Beta-2 adrenergic receptor | |
---|---|
Transduction mechanisms | Primary:
Gs Secondary: Gi/o |
Primary endogenous agonists | epinephrine, norepinephrine |
Agonists | isoprenaline, salbutamol, salmeterol, others |
Antagonists | carvedilol, propranolol, labetalol, others |
Inverse agonists | N/A |
Positive allosteric modulators | Zn2+ (low concentrations) |
Negative allosteric modulators | Zn2+ (high concentrations) |
External resources | |
IUPHAR/BPS | 29 |
DrugBank | P07550 |
HMDB | HMDBP01634 |
* denotes selective antagonist to the receptor.
Beta-2 adrenergic receptor has been shown to interact with: