Beta-1 adrenergic receptor

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The beta-1 adrenergic receptor (β1 adrenoceptor), also known as ADRB1, is a beta-adrenergic receptor, and also denotes the human gene encoding it.[1] It is a G-protein coupled receptor associated with the Gs heterotrimeric G-protein and is expressed predominantly in cardiac tissue.

## Contents

* 1 Receptor
* 1.1 Actions
* 1.2 Agonists
* 1.3 Antagonists
* 1.4 Mechanism in cardiac myocytes
* 2 Gene
* 3 Interactions
* 4 See also
* 5 References
* 6 Further reading
* 7 External links

## Receptor

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### Actions

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Actions of the β1 receptor include:

Effect/Tissue

Muscular  | Increase cardiac output | cardiac muscle
Increase heart rate (chronotropic effect)  | sinoatrial node (SA node) [2]
Increase atrial contractility (inotropic effect)  | cardiac muscle
Increases contractility and automaticity | ventricular cardiac muscle [2]
Increases conduction and automaticity | atrioventricular node (AV node)[2]
Relaxation  | urinary bladder wall[3]
Exocrine  | Renin release  | juxtaglomerular cells.[2]
stimulate viscous, amylase-filled secretions  |

salivary glands[4]

Other  | Lipolysis | adipose tissue.[2]

The receptor is also present in the cerebral cortex.

### Agonists

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Isoprenaline has higher affinity for β1 than adrenaline, which, in turn, binds with higher affinity than noradrenaline at physiologic concentrations. Selective agonists to the beta-1 receptor are:

* Denopamine
* Dobutamine[4] (in cardiogenic shock)
* Xamoterol[4] (cardiac stimulant)

### Antagonists

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(Beta blockers) β1-selective antagonists include:

* Acebutolol (in hypertension, angina pectoris and arrhythmias)
* Atenolol[4] (in hypertension, coronary heart disease, arrhythmias and myocardial infarction)
* Betaxolol (in hypertension and glaucoma)
* Bisoprolol[5] (in hypertension, coronary heart disease, arrhythmias, myocardial infarction and ischemic heart diseases)
* Esmolol (in arrhythmias)
* Metoprolol[4] (in hypertension, coronary heart disease, myocardial infarction and heart failure)
* Nebivolol (in hypertension)
* Vortioxetine (antidepressant)

### Mechanism in cardiac myocytes

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Gs exerts its effects via two pathways. Firstly, it directly opens L-type calcium channels (LTCC) in the plasma membrane. Secondly, it renders adenylate cyclase activated, resulting in an increase of cAMP, activating protein kinase A (PKA) which in turn phosphorylates several targets, such as phospholamban, LTCC, Troponin I (TnI), and potassium channels. Phospholamban phosphorylates deactivates its function which is normally inhibition of SERCA on the sarcoplasmic reticulum (SR) in cardiac myocytes. Due to this, more calcium enters the SR and is therefore available for the next contraction. LTCC phosphorylatation increases its open probability and therefore allows more calcium to enter the myocyte upon cell depolarisation. Both of these mechanisms increase the available calcium for contraction and therefore increase inotropy. Conversely, TnI phosphorylation results in its facilitated dissociation of calcium from troponin C (TnC) which fastens the muscle relaxation (positive lusitropy). Potassium channel phosphorylates increases its open probability which results in shorter refractory period (because the cell repolarises faster), also increasing lusitropy. Furthermore, in nodal cells such as in the SA node, cAMP directly binds to and opens the HCN channels, increasing their open probability, which increases chronotropy.[6]

## Gene

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Specific polymorphisms in the ADRB1 gene have been shown to affect the resting heart rate and can be involved in heart failure.[1]

## Interactions

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Beta-1 adrenergic receptor has been shown to interact with DLG4[7] and GIPC1.[8] Interaction between testosterone and β-1 ARs have been shown in anxiolytic behaviors in the basolateral amygdala.[9]

## See also

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* Other adrenergic receptors
* Alpha-1 adrenergic receptor
* Alpha-2 adrenergic receptor
* Beta-2 adrenergic receptor
* Beta-3 adrenergic receptor

## References

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1. ↑ 1.0 1.1 "Entrez Gene: ADRB1 adrenergic, beta-1-, receptor".
2. ↑ 2.0 2.1 2.2 2.3 2.4 Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 0-87893-725-0.
3. ↑ Moro C, Tajouri L, Chess-Williams R (January 2013). "Adrenoceptor function and expression in bladder urothelium and lamina propria". Urology. 81 (1): 211.e1–7. doi:10.1016/j.urology.2012.09.011. PMID 23200975.
4. ↑ 4.0 4.1 4.2 4.3 4.4 Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 163
5. ↑ American Society of Health-System Pharmacists, Inc. (2005-01-01). "Bisoprolol". MedlinePlus Drug Information. U.S. National Library of Medicine, National Institutes of Health. Archived from the original on 2008-05-20. Retrieved 2008-06-06.
6. ↑ Medical physiology : a cellular and molecular approach. Boron, Walter F.,, Boulpaep, Emile L., (Updated second ed.). Philadelphia, PA. ISBN 9781437717532. OCLC 756281854.
7. ↑ Hu LA, Tang Y, Miller WE, Cong M, Lau AG, Lefkowitz RJ, Hall RA (Dec 2000). "beta 1-adrenergic receptor association with PSD-95. Inhibition of receptor internalization and facilitation of beta 1-adrenergic receptor interaction with N-methyl-D-aspartate receptors". The Journal of Biological Chemistry. 275 (49): 38659–66. doi:10.1074/jbc.M005938200. PMID 10995758.
8. ↑ Hu LA, Chen W, Martin NP, Whalen EJ, Premont RT, Lefkowitz RJ (Jul 2003). "GIPC interacts with the beta1-adrenergic receptor and regulates beta1-adrenergic receptor-mediated ERK activation". The Journal of Biological Chemistry. 278 (28): 26295–301. doi:10.1074/jbc.M212352200. PMID 12724327.
9. ↑ Mard-Soltani M, Kesmati M, Khajehpour L, Rasekh A, Shamshirgar-Zadeh A (April 2012). "Interaction between Anxiolytic Effects of Testosterone and β-1 Adrenoceptors of Basolateral Amygdala". International Journal of Pharmacology. 8 (5): 344–354. doi:10.3923/ijp.2012.344.354.

## Further reading

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* Frielle T, Kobilka B, Lefkowitz RJ, Caron MG (Jul 1988). "Human beta 1- and beta 2-adrenergic receptors: structurally and functionally related receptors derived from distinct genes". Trends in Neurosciences. 11 (7): 321–4. doi:10.1016/0166-2236(88)90095-1. PMID 2465637.
* Muszkat M (Aug 2007). "Interethnic differences in drug response: the contribution of genetic variability in beta adrenergic receptor and cytochrome P4502C9". Clinical Pharmacology and Therapeutics. 82 (2): 215–8. doi:10.1038/sj.clpt.6100142. PMID 17329986.
* Yang-Feng TL, Xue FY, Zhong WW, Cotecchia S, Frielle T, Caron MG, Lefkowitz RJ, Francke U (Feb 1990). "Chromosomal organization of adrenergic receptor genes". Proceedings of the National Academy of Sciences of the United States of America. 87 (4): 1516–20. doi:10.1073/pnas.87.4.1516. PMC 53506. PMID 2154750.
* Forse RA, Leibel R, Gagner M (Jan 1989). "The effect of Escherichia coli endotoxin on the adrenergic control of lipolysis in the human adipocyte". The Journal of Surgical Research. 46 (1): 41–8. doi:10.1016/0022-4804(89)90180-7. PMID 2536864.
* Frielle T, Collins S, Daniel KW, Caron MG, Lefkowitz RJ, Kobilka BK (Nov 1987). "Cloning of the cDNA for the human beta 1-adrenergic receptor". Proceedings of the National Academy of Sciences of the United States of America. 84 (22): 7920–4. doi:10.1073/pnas.84.22.7920. PMC 299447. PMID 2825170.
* Stiles GL, Strasser RH, Lavin TN, Jones LR, Caron MG, Lefkowitz RJ (Jul 1983). "The cardiac beta-adrenergic receptor. Structural similarities of beta 1 and beta 2 receptor subtypes demonstrated by photoaffinity labeling". The Journal of Biological Chemistry. 258 (13): 8443–9. PMID 6305985.
* Hoehe MR, Otterud B, Hsieh WT, Martinez MM, Stauffer D, Holik J, Berrettini WH, Byerley WF, Gershon ES, Lalouel JM (Jun 1995). "Genetic mapping of adrenergic receptor genes in humans". Journal of Molecular Medicine. 73 (6): 299–306. doi:10.1007/BF00231616. PMID 7583452.
* Elies R, Ferrari I, Wallukat G, Lebesgue D, Chiale P, Elizari M, Rosenbaum M, Hoebeke J, Levin MJ (Nov 1996). "Structural and functional analysis of the B cell epitopes recognized by anti-receptor autoantibodies in patients with Chagas' disease". Journal of Immunology. 157 (9): 4203–11. PMID 8892658.
* Oldenhof J, Vickery R, Anafi M, Oak J, Ray A, Schoots O, Pawson T, von Zastrow M, Van Tol HH (Nov 1998). "SH3 binding domains in the dopamine D4 receptor". Biochemistry. 37 (45): 15726–36. doi:10.1021/bi981634+. PMID 9843378.
* Mason DA, Moore JD, Green SA, Liggett SB (Apr 1999). "A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor". The Journal of Biological Chemistry. 274 (18): 12670–4. doi:10.1074/jbc.274.18.12670. PMID 10212248.
* Moore JD, Mason DA, Green SA, Hsu J, Liggett SB (Sep 1999). "Racial differences in the frequencies of cardiac beta(1)-adrenergic receptor polymorphisms: analysis of c145A>G and c1165G>C". Human Mutation. 14 (3): 271. doi:10.1002/(SICI)1098-1004(1999)14:3<271::AID-HUMU14>3.0.CO;2-Q. PMID 10477438.
* Tang Y, Hu LA, Miller WE, Ringstad N, Hall RA, Pitcher JA, DeCamilli P, Lefkowitz RJ (Oct 1999). "Identification of the endophilins (SH3p4/p8/p13) as novel binding partners for the beta1-adrenergic receptor". Proceedings of the National Academy of Sciences of the United States of America. 96 (22): 12559–64. doi:10.1073/pnas.96.22.12559. PMC 22990. PMID 10535961.
* Podlowski S, Wenzel K, Luther HP, Müller J, Bramlage P, Baumann G, Felix SB, Speer A, Hetzer R, Köpke K, Hoehe MR, Wallukat G (2000). "Beta1-adrenoceptor gene variations: a role in idiopathic dilated cardiomyopathy?". Journal of Molecular Medicine. 78 (2): 87–93. doi:10.1007/s001090000080. PMID 10794544.
* Shiina T, Kawasaki A, Nagao T, Kurose H (Sep 2000). "Interaction with beta-arrestin determines the difference in internalization behavor between beta1- and beta2-adrenergic receptors". The Journal of Biological Chemistry. 275 (37): 29082–90. doi:10.1074/jbc.M909757199. PMID 10862778.
* Hu LA, Tang Y, Miller WE, Cong M, Lau AG, Lefkowitz RJ, Hall RA (Dec 2000). "beta 1-adrenergic receptor association with PSD-95. Inhibition of receptor internalization and facilitation of beta 1-adrenergic receptor interaction with N-methyl-D-aspartate receptors". The Journal of Biological Chemistry. 275 (49): 38659–66. doi:10.1074/jbc.M005938200. PMID 10995758.
* Börjesson M, Magnusson Y, Hjalmarson A, Andersson B (Nov 2000). "A novel polymorphism in the gene coding for the beta(1)-adrenergic receptor associated with survival in patients with heart failure". European Heart Journal. 21 (22): 1853–8. doi:10.1053/euhj.1999.1994. PMID 11052857.
* Xu J, Paquet M, Lau AG, Wood JD, Ross CA, Hall RA (Nov 2001). "beta 1-adrenergic receptor association with the synaptic scaffolding protein membrane-associated guanylate kinase inverted-2 (MAGI-2). Differential regulation of receptor internalization by MAGI-2 and PSD-95". The Journal of Biological Chemistry. 276 (44): 41310–7. doi:10.1074/jbc.M107480200. PMID 11526121.
* Hu LA, Chen W, Premont RT, Cong M, Lefkowitz RJ (Jan 2002). "G protein-coupled receptor kinase 5 regulates beta 1-adrenergic receptor association with PSD-95". The Journal of Biological Chemistry. 277 (2): 1607–13. doi:10.1074/jbc.M107297200. PMID 11700307.
* Ranade K, Jorgenson E, Sheu WH, Pei D, Hsiung CA, Chiang FT, Chen YD, Pratt R, Olshen RA, Curb D, Cox DR, Botstein D, Risch N (Apr 2002). "A polymorphism in the beta1 adrenergic receptor is associated with resting heart rate". American Journal of Human Genetics. 70 (4): 935–42. doi:10.1086/339621. PMC 379121. PMID 11854867.

## External links

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* Human ADRB1 genome location and ADRB1 gene details page in the UCSC Genome Browser.
* "β1-adrenoceptor". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.

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Cell surface receptor: G protein-coupled receptors

Class A: Rhodopsin-like

| Neurotransmitter|

| Adrenergic|

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Class F: Frizzled & Smoothened

| Frizzled|

* Frizzled (1
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Smoothened|

* Smoothened

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