β 1 adrenoceptor

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β 1 adrenoceptor
β1 adrenoceptor
3D structural model of the β 1 -adrenoceptor with bound agonist isoprenaline based on crystal structure data

Existing structure data : PDB  2Y00 , PDB  2Y01 , PDB  2Y02 , PDB  2Y03 , PDB  2Y04 , PDB  2VT4

Properties of human protein
Mass / length primary structure 477 AS ; 51.3  kDa
Secondary to quaternary structure 7TM
Identifier
Gene names ADRB1 , ADRB1R, B1AR
External IDs
Occurrence
Parent taxon Vertebrates

The β 1 -adrenergic receptor , often also called β 1 -adrenergic receptor , is a cell membrane- bound protein from the beta-adrenoceptors belonging to the family of G-protein-coupled receptors . It is activated by the hormone adrenaline and is responsible, among other things, for its effect on the heart . The β 1 -adrenoceptor is the molecular target of one of the most important groups of drugs , the beta blockers .

Distribution in the animal kingdom

The β 1 -adrenoceptor shows widespread distribution within the vertebrate sub-tribe . It was found in fish , amphibians , reptiles , birds and mammals . The developmental development of the β 1 -adrenoceptors and the splitting off to other β-adrenoceptors through gene duplication can be extrapolated to the late Neoproterozoic or the early Paleozoic .

Occurrence and function in humans

In the human organism, the β 1 -adrenoceptor is found particularly in the heart. In the heart, it is the dominant β-adrenoceptor with a share of 70 to 80%. It is primarily responsible for the contractility-increasing (positive inotropy ), heart rate-increasing (positive chronotropy ), stimulation conduction accelerating (positive dromotropy ) and stimulus threshold-lowering effects (positive bathmotropy ) of the adrenaline on the heart.

The β 1 -adrenoceptor is also found on cells in the kidney, the juxtaglomerular cells . Renin is released through stimulation .

genetics

The β 1 -adrenoceptor is the intron-free ADRB1 - gene coded. The human ADRB1 gene is located on chromosome 10 in the gene locus 10q24-q26. Polymorphisms of the gene have been linked to heart failure and changes in the effectiveness of beta blockers , among other things .

biochemistry

structure

The β 1 -adrenoceptor was one of the first G-protein-coupled receptors whose structure could be elucidated with the help of X-ray crystallography . As a characteristic motif, the β 1 -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 1 adrenoceptor, similar to the β 2 adrenoceptor , has another 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 1 -adrenoceptor is activated by binding its own ligands adrenaline and noradrenaline. The binding of an agonistic ligand contracts the ligand binding site and 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 . Via the β 1 -adrenoceptor, G s proteins are preferably activated, which in turn activate adenylyl cyclases and increase the intracellular cAMP level.

pharmacology

Structure of the β 1 -adrenoceptor antagonist metoprolol

The β 1 -adrenoceptor is one of the pharmacologically most important target structures for drug development. Antagonists of the β 1 -adrenoceptor, the so-called beta-blockers , which include the drugs atenolol , bisoprolol , carvedilol , metoprolol , nebivolol , propranolol , sotalol and timolol include, in particular, in the treatment of hypertension , of coronary heart disease , of heart failure , of Arrhythmias and migraines are used.

β 1 -adrenoceptor agonists such as adrenaline, noradrenaline and dobutamine are used in anesthesia as well as intensive and emergency medicine .

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. ↑ Jahns R, Boivin V, Lohse MJ: β 1 -Adrenergic receptor function, autoimmunity, and pathogenesis of dilated cardiomyopathy . In: Trends Cardiovasc. Med. . 16, No. 1, January 2006, pp. 20-24. doi : 10.1016 / j.tcm.2005.11.002 . PMID 16387626 .
  3. ↑ Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20: 2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 0-87893-725-0 .
  4. ↑ Frielle T, Collins S, Daniel KW, Caron MG, Lefkowitz RJ, Kobilka BK: Cloning of the cDNA for the human beta 1-adrenergic receptor . In: Proc Natl Acad Sci USA . 84, No. 22, November 1987, pp. 7920-7924. PMID 2825170 .
  5. ↑ Leineweber K, Heusch G: Beta 1- and beta 2-adrenoceptor polymorphisms and cardiovascular diseases . In: Br J Pharmacol . 158, No. 1, September 2009, pp. 61-69. doi : 10.1111 / j.1476-5381.2009.00187.x . PMID 19422376 .
  6. ^ Warne T, Serrano-Vega MJ, Baker JG et al. : Structure of a beta1-adrenergic G-protein-coupled receptor . In: Nature . 454, No. 7203, July 2008, pp. 486-491. doi : 10.1038 / nature07101 . PMID 18594507 .
  7. ↑ Huang J, Chen S, Zhang JJ, Huang XY: Crystal structure of oligomeric β1-adrenergic G protein-coupled receptors in ligand-free basal state . In: Nat. Struct. Mol. Biol . 2013. doi : 10.1038 / nsmb.2504 . PMID 23435379 .
  8. ↑ Warne T, Moukhametzianov R, Baker JG et al. : The structural basis for agonist and partial agonist action on a β (1) -adrenergic receptor . In: Nature . 469, No. 7329, January 2011, pp. 241-244. doi : 10.1038 / nature09746 . PMID 21228877 .