Beta-2 adrenergic receptor

Gene

The gene is intronless. Different polymorphic forms, point mutations, and/or downregulation of this gene are associated with nocturnal asthma, obesity and type 2 diabetes.

Structure

The 3D crystallographic structure (see figure and links to the right) of the β2-adrenergic receptor has been determined 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.

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 CaV1.2. 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.

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. 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

2 receptor include:--

Musculoskeletal system

Activation of the β2 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 β2 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 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.

Circulatory system

• Heart muscle contraction
• Increase cardiac output (minor degree compared to β1).
  • Increases heart rate in sinoatrial node (SA node) (chronotropic effect).
  • Increases atrial cardiac muscle contractility. (inotropic effect).
  • Increases contractility and automaticity of ventricular cardiac muscle.
• Dilate hepatic artery.
• Dilate arterioles to skeletal muscle.

Eye

In the normal eye, beta-2 stimulation by salbutamol increases intraocular pressure via net:

• Increase in production of aqueous humour by the ciliary process,
• Subsequent increased pressure-dependent uveoscleral outflow of humour, despite reduced drainage of humour via the Canal of Schlemm.

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.

Digestive system

• Glycogenolysis and gluconeogenesis in liver.
• Glycogenolysis and lactate release in skeletal muscle.
• Contract sphincters of Gastrointestinal tract.
• Thickened secretions from salivary glands.
• Insulin and glucagon secretion from pancreas.

Other

• Inhibit histamine-release from mast cells.
• Increase protein content of secretions from lacrimal glands.
• Receptor also present in cerebellum.
• Bronchiole dilation (targeted while treating asthma attacks)
• Involved in brain - immune - communication

Ligands

Agonists

Secondary: Gi/o Main article: Beta2-adrenergic agonist

Spasmolytics used in [[asthma]] and [[Chronic obstructive pulmonary disease|COPD]]

• Short-acting β2 agonists (SABA)
  • bitolterol
  • fenoterol
  • hexoprenaline
  • isoprenaline (INN) or isoproterenol (USAN)
  • levosalbutamol (INN) or levalbuterol (USAN)
  • orciprenaline (INN) or metaproterenol (USAN)
  • pirbuterol
  • procaterol
  • salbutamol (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
  • milveterol (GSK 159797)
  • olodaterol
  • vilanterol (GSK 642444)

[[Tocolytic]] agents

• Short-acting β2 agonists (SABA)
  • fenoterol
  • hexoprenaline
  • isoxsuprine
  • ritodrine
  • salbutamol (INN) or albuterol (USAN)
  • terbutaline

β₂ agonists used for other purposes

• zilpaterol

Antagonists

(Beta blockers)

• 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
• Cellular swelling

Interactions

Beta-2 adrenergic receptor has been shown to interact with:

• AKAP12,
• OPRD1,
• Grb2,
• SNX27 and
• SLC9A3R1.

References

References

1. (January 2006). "Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation". The Journal of Allergy and Clinical Immunology.
2. "The Nobel Prize in Chemistry 2012".
3. "The Nobel Prize in Chemistry 2012".
4. "The Nobel Prize in Chemistry 2012".
5. "Entrez Gene: ADRB2 adrenoceptor beta 2, surface".
6. "Entrez Gene: ADRB2 adrenergic, beta-2-, receptor, surface".
7. (2007). "High-resolution crystal structure of an engineered human β₂-adrenergic G protein-coupled receptor". Science.
8. (2007). "GPCR engineering yields high-resolution structural insights into β₂-adrenergic receptor function". Science.
9. (Nov 2007). "Crystal structure of the human beta2 adrenergic G-protein-coupled receptor". Nature.
10. (1 October 2015). "Dissecting the Structure of Membrane Proteins". [[Gen. Eng. Biotechnol. News.
11. (July 2011). "Crystal structure of the β2 adrenergic receptor-Gs protein complex". Nature.
12. (Dec 2006). "Molecular dynamics of a biophysical model for beta2-adrenergic and G protein-coupled receptor activation". Journal of Molecular Graphics & Modelling.
13. (Nov 2000). "G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels". Biophysical Journal.
14. (Aug 2002). "Protein kinase A-mediated phosphorylation of the beta 2-adrenergic receptor regulates its coupling to Gs and Gi. Demonstration in a reconstituted system". The Journal of Biological Chemistry.
15. (June 2021). "Visualization of β-adrenergic receptor dynamics and differential localization in cardiomyocytes". Proceedings of the National Academy of Sciences of the United States of America.
16. (2004). "Neuroscience". Sinauer.
17. (1995). "Response of guinea pig smooth and striated urethral sphincter to cromakalim, prazosin, nifedipine, nitroprusside, and electrical stimulation". Neurourology and Urodynamics.
18. (January 2013). "Adrenoceptor function and expression in bladder urothelium and lamina propria". Urology.
19. (2003). "Pharmacology". Churchill Livingstone.
20. (2003). "Pharmacology". Churchill Livingstone.
21. (December 2002). "beta-Agonists and metabolism". The Journal of Allergy and Clinical Immunology.
22. (July 1992). "Anabolic effects of clenbuterol on skeletal muscle are mediated by beta 2-adrenoceptor activation". The American Journal of Physiology.
23. (April 2008). "Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure". The Journal of Heart and Lung Transplantation.
24. (June 2008). "The rush to adrenaline: drugs in sport acting on the beta-adrenergic system". British Journal of Pharmacology.
25. "Clenbuterol". Drug Enforcement Agency.
26. "Food and Drugs - ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS". U.S. Food and Drug Administration.
27. (Dec 2000). "The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system". Pharmacological Reviews.
28. (2007). "ultra-long-acting beta2-adrenoceptor agonists: an emerging therapeutic option for asthma and COPD?". Drugs.
29. (June 2019). "Mechanism of β₂AR regulation by an intracellular positive allosteric modulator". Science.
30. (August 2024). "Cell swelling enhances ligand-driven β-adrenergic signaling". Nature Communications.
31. (Jun 2001). "The scaffold protein gravin (cAMP-dependent protein kinase-anchoring protein 250) binds the beta 2-adrenergic receptor via the receptor cytoplasmic Arg-329 to Leu-413 domain and provides a mobile scaffold during desensitization". The Journal of Biological Chemistry.
32. (Jan 1999). "Dynamic complexes of beta2-adrenergic receptors with protein kinases and phosphatases and the role of gravin". The Journal of Biological Chemistry.
33. (Apr 2001). "Monitoring receptor oligomerization using time-resolved fluorescence resonance energy transfer and bioluminescence resonance energy transfer. The human delta -opioid receptor displays constitutive oligomerization at the cell surface, which is not regulated by receptor occupancy". The Journal of Biological Chemistry.
34. (Dec 1998). "Insulin stimulates sequestration of beta-adrenergic receptors and enhanced association of beta-adrenergic receptors with Grb2 via tyrosine 350". The Journal of Biological Chemistry.
35. (Jun 2011). "SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors". Nature Cell Biology.
36. (May 2002). "Structural determinants of the Na+/H+ exchanger regulatory factor interaction with the beta 2 adrenergic and platelet-derived growth factor receptors". The Journal of Biological Chemistry.
37. (Jul 1998). "A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins". Proceedings of the National Academy of Sciences of the United States of America.
38. (Apr 1998). "The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange". Nature.