β 2 adrenoceptor

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β 2 adrenoceptor
β2 adrenoceptor
3D structural model of the β 2 -adrenoceptor with the inverse agonist carazolol

Existing structure data : PDB  2RH1 , PDB  3P0G , PDB  3PDS , PDB  3NY8 , PDB  3NY9 , PDB  3NYA , PDB  3KJ6 , PDB  2R4R , PDB  2R4S

Properties of human protein
Mass / length primary structure 413 AS ; 46.5  kDa
Secondary to quaternary structure 7TM
Identifier
Gene names ADRB2 , ADRB2R, B2AR
External IDs
Occurrence
Parent taxon Vertebrates

The β 2 -adrenergic receptor , often also called the β 2 -adrenergic receptor , is a cell membrane- bound protein from the beta- adrenergic receptors belonging to the family of G-protein-coupled receptors . Along with the visual pigment rhodopsin, it is the best-studied protein in this family. The β 2 -adrenoceptor is activated by the hormones adrenaline and isoprenaline and is responsible, among other things, for its smooth muscle relaxing, glucose- releasing and muscle anabolic effect.

Occurrence

The β 2 -adrenoceptor can be detected in many representatives of the vertebrate sub-tribe and occurs ubiquitously in representatives of the mammalian class . The developmental development of the β 2 -adrenoceptors and the splitting off to other β-adrenoceptors through gene duplication can be extrapolated to the late Neoproterozoic or the early Paleozoic .

In the human body of β is 2 adrenoceptor widespread and can be found in particular in the cell membranes of the cells of the smooth muscle, the nerve cells and fat cells . In addition to the dominant β 1 -adrenoceptor , it is also found in large quantities in the heart .

biochemistry

genetics

The β 2 -adrenoceptor is the intron-free ADRB2 - gene coded. The human ADRB2 gene is located on chromosome 5 in the gene locus 5q31-q32. Polymorphisms and point mutations of the gene are associated with asthma , obesity and cardiovascular diseases , among other things .

structure

The β 2 -adrenoceptor is one of the few G-protein-coupled receptors whose structure could be clarified with the help of X-ray crystallography . For him structure data are available for both the active and the inactive state, after stabilization by fusion with the relatively easy to be crystallized lysozyme of the T4 phage (T4 lysozyme) or by complexing with the aid of F from - antibody fragments or single domain antibodies obtained . As a characteristic motif, the β 2 -adrenoceptor, like all other known G-protein-coupled receptors, carries seven α-helices spanning the cell membrane . As with rhodopsin, an eighth α-helix connects to the intracellular end of the transmembrane helix 7. In addition, the β 2 adrenoceptor has a further α-helical structural motif, which is located extracellularly between the transmembrane helices 4 and 5. A ligand binding site, to which the body's own ligand adrenaline and numerous drugs bind, is on the outer side of the transmembrane helices. The loops inside the cell, on the other hand, carry binding sites for the effector proteins involved in signal transmission, in particular G proteins .

Receptor activation

The β 2 -adrenoceptor is activated by the binding of its own ligand, adrenaline. To a lesser extent, i.e. with an approximately 30-fold lower affinity , the norepinephrine , which mainly functions as a neurotransmitter , also binds and activates this receptor. The binding of these ligands stabilizes the active state of the receptor. In this state, the receptor is able to activate intracellularly bound G proteins and thus start a signal transduction cascade . The β 2 adrenoceptor is preferably used to activate G s proteins, which in turn activate adenylyl cyclases and increase the intracellular cAMP level. But G proteins of the G i / o family can also couple with this receptor. Additional interaction partners of the β 2 -adrenoceptor are, for example, β-arrestin and G-protein-coupled receptor kinases .

function

The β 2 -adrenoceptor is mainly responsible for the relaxation of the smooth muscles through adrenaline. Activation of β 2 -adrenoceptor, for example, leads to relaxation of the bronchi , the uterus and the intestine . In the blood vessels , the β 2 -adrenoceptor is the dominant β-adrenoceptor. Here, too, it is primarily responsible for the relaxing active component of adrenaline and thus an antagonist of the α 1 -adrenoceptors . Not only the β 2 -adrenoceptors of the smooth muscles of the blood vessels, but also the endothelial cells that release nitric oxide are involved in vasorelaxation .

pharmacology

β 2 -adrenoceptor agonist salbutamol

The β 2 -adrenoceptor is one of the pharmacologically most important target structures for drug development. In addition to the body's own ligands adrenaline and noradrenaline, synthetic agonists in particular are used therapeutically. These are used, for example, Clenbuterol , Fenoterol , Reproterol , Salbutamol , Salmeterol and Terbutaline , for the treatment of bronchial asthma and other respiratory diseases. In obstetrics, β 2 -adrenoceptor agonists, such as fenoterol, are used as tocolytics . The lipolytic and muscle anabolic effects of the β 2 -adrenoceptor agonists are used illegally in animal breeding and doping in competitive sports .

In contrast to the agonists, selective antagonists of the β 2 -adrenoceptor have no therapeutic significance. Non-selective beta-blocker , both β 1 - and β 2 block adrenoceptors, such as propranolol , are used in the treatment of hypertension , of heart failure and coronary heart disease application.

Individual evidence

  1. ↑ Aris-Brosou S, Chen X, Perry SF, Moon TW: Timing of the functional diversification of alpha- and beta-adrenoceptors in fish and other vertebrates . In: Ann. NY Acad. Sci. . 1163, April 2009, pp. 343-347. doi : 10.1111 / j.1749-6632.2009.04451.x . PMID 19456356 .
  2. ↑ Brodde OE, Bruck H, Leineweber K: Cardiac adrenoceptors: physiological and pathophysiological relevance . In: J Pharmacol Sci . 100, No. 5, 2006, pp. 323-337. PMID 16612046 .
  3. ↑ Kobilka BK, Dixon RA, Frielle T, et al. : cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor . In: Proc. Natl. Acad. Sci. USA . 84, No. 1, January 1987, pp. 46-50. PMID 3025863 . PMC 304138 (free full text).
  4. ↑ Turki J, Pak J, Green SA, Martin RJ, Liggett SB: Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype . In: J. Clin. Invest. . 95, No. 4, April 1995, pp. 1635-1641. doi : 10.1172 / JCI117838 . PMID 7706471 . PMC 295666 (free full text).
  5. ↑ Large V, Hellström L, Reynisdottir S, et al. : Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function . In: J. Clin. Invest. . 100, No. 12, December 1997, pp. 3005-3013. doi : 10.1172 / JCI119854 . PMID 9399946 . PMC 508512 (free full text).
  6. ^ Eisenach JH, Wittwer ED: β-Adrenoceptor gene variation and intermediate physiological traits: prediction of distant phenotype . In: Exp. Physiol. . 95, No. 7, July 2010, pp. 757-764. doi : 10.1113 / expphysiol.2009.048330 . PMID 20382665 .
  7. ↑ Cherezov V, Rosenbaum DM, Hanson MA, et al. : High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor . In: Science . 318, No. 5854, November 2007, pp. 1258-1265. doi : 10.1126 / science.1150577 . PMID 17962520 . PMC 2583103 (free full text).
  8. ↑ Rasmussen SG, Choi HJ, Rosenbaum DM, et al. : Crystal structure of the human beta2 adrenergic G-protein-coupled receptor . In: Nature . 450, No. 7168, November 2007, pp. 383-387. doi : 10.1038 / nature06325 . PMID 17952055 .
  9. ↑ Rasmussen SG, Choi HJ, Fung JJ, et al. : Structure of a nanobody-stabilized active state of the β (2) adrenoceptor . In: Nature . 469, No. 7329, January 2011, pp. 175-180. doi : 10.1038 / nature09648 . PMID 21228869 .
  10. ↑ Guimarães S, Moura D: Vascular adrenoceptors: an update . In: Pharmacol. Rev. . 53, No. 2, June 2001, pp. 319-56. PMID 11356987 .