Beta-1 adrenergic receptor explained

The beta-1 adrenergic receptor (β₁ adrenoceptor), also known as ADRB1, can refer to either the protein-encoding gene (gene ADRB1) or one of the four adrenergic receptors.^[1] It is a G-protein coupled receptor associated with the Gs heterotrimeric G-protein that is expressed predominantly in cardiac tissue. In addition to cardiac tissue, beta-1 adrenergic receptors are also expressed in the cerebral cortex.

Historical Context

W. B. Cannon postulated that there were two chemical transmitters or sympathins while studying the sympathetic nervous system in 1933. These E and I sympathins were involved with excitatory and inhibitory responses. In 1948, Raymond Ahlquist published a manuscript in the American Journal of Physiology establishing the idea of adrenaline having distinct actions on both alpha and beta receptors. Shortly afterward, Eli Lilly Laboratories synthesized the first beta-blocker, dichloroisoproterenol.

General Information

Structure

ADRB-1 is a transmembrane protein that belongs to the G-Protein-Coupled Receptor (GPCR) family.^{[2] [3]} GPCRs play a key role in cell signaling pathways and are primarily known for their seven transmembrane (7TM) helices, which have a cylindrical structure and span the membrane. The 7TM domains have three intracellular and three extracellular loops that connect these domains to one another. The extracellular loops contain sites for ligand binding on N-terminus of the receptor and the intracellular loops and C-terminus interact with signaling proteins, such as G-proteins. The extracellular loops also contain several sites for post-translational modification and are involved in ligand binding. The third intracellular loop is the largest and contains phosphorylation sites for signaling regulation. As the name suggests, GPCRs are coupled to G-proteins that are heterotrimeric in nature. Heterotrimeric G-proteins consist of three subunits: alpha, beta, and gamma.^[4] Upon the binding of a ligand to the extracellular domain of the GPCR, a conformational change is induced in the receptor that allows it to interact with the alpha-subunit of the G-protein. Following this interaction, the G-alpha subunit exchanges GDP for GTP, becomes active, and dissociates from the beta and gamma subunits. The free alpha subunit is then able to activate downstream signaling pathways (detail more in interactions and pathway).

Function

Pathways

ADRB-1 is activated by the catecholamines adrenaline and noradrenaline. Once these ligands bind, the ADRB-1 receptor activates several different signaling pathways and interactions. Some of the most well-known pathways are:

1. Adenylyl Cyclase: When a ligand binds to the ADRB-1 Receptor, the alpha-subunit of the heterotrimeric G-protein gets activated, which in turn, activates the enzyme adenylyl cyclase. Adenylyl cyclase then catalyzes the conversion of ATP to cyclic AMP (cAMP), which activates downstream effectors such as Protein Kinase A (PKA).
2. cAMP Activation of PKA: cAMP generated by adenylyl cyclase activates PKA, which then phosphorylates numerous downstream targets such as ion channels, other enzymes, and transcription factors .
3. Beta-arrestins: Activation of the ADRB-1 receptor can lead to the recruitment of Beta-arrestins, which are used to activate signaling pathways independent of G-proteins. An example of an independent pathway is the MAPK (mitogen-activated protein kinase) pathways.
4. Calcium signaling: ADRB-1 signaling also activates the Gq/11 family of G proteins, which is a subfamily of heterotrimeric G proteins that activates phospholipase C (PLC). PLC cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 binds to IP3 receptors on the endoplasmic reticulum, which then leads to the release of calcium ions (Ca2+) into the cytoplasm, resulting in the activation of downstream signaling pathways.

Summary of Interactions

Actions of the β₁ receptor include:

System	Effect	Tissue
Muscular	Increases cardiac output	Cardiac muscle
	Increases heart rate (chronotropic effect)	Sinoatrial node (SA node) ^[5]
	Increases atrial contractility (inotropic effect)	Cardiac muscle
	Increases contractility and automaticity	Ventricular cardiac muscle
	Increases conduction and automaticity	Atrioventricular node (AV node)
	Relaxation	Urinary bladder wall^[6]
Exocrine	Releases renin	Juxtaglomerular cells.
	Stimulates viscous, amylase-filled secretions	Salivary glands^[7]
Other	Lipolysis	Adipose tissue

The receptor is also present in the cerebral cortex.

Other pathways that play ADRB-1 receptor plays an important role in:

1. Regulation of peripheral clock and central circadian clock synchronization: The suprachiasmatic nucleus (SCN) receives light information from the eyes and synchronizes the peripheral clocks to the central circadian clock through the release of different neuropeptides and hormones.^[8] ADRB-1 receptors can play a role in modulating the release of neuropeptides like vasoactive intestinal peptide (VIP) and arginine vasopressin (AVP) from the SCN, which can then synchronize peripheral clocks.
2. Regulation of glucose metabolism: The regulation of glucose metabolism is known to be linked with ADRB-1 receptor signaling.^[9] The signal transduction pathway that is activated through the ADRB-1 receptor can regulate the expression of clock genes and glucose transporters. The disregulation of ADRB-1 receptor signaling has been implicated in metabolic disorders such as diabetes and obesity.
3. ADRB-1 Receptor and Rhythmic Control of Immunity: Circadian oscillations in catecholamine signals influence various cellular targets which express adrenergic receptors, including immune cells. The adrenergic system regulates a range of physiological functions which are carried out through catecholamine production. Humans are found to have low circulating catecholamine levels during the night and high levels during the day, while rodents exhibit the opposite pattern. Studies demonstrating the patterns of norepinephrine levels indicate that there is no circadian rhythmicity. Circulating rhythms in epinephrine, however, appear to be circadian and are regulated by the HPA axis:
   1. Cyclic variation in HPA signals are likely important in driving diurnal oscillations in adrenaline.
   2. The most well-characterized means through which adrenergic signals exert circadian control over immunity is by cell-trafficking regulation. Variation in the number of white blood cells seemed to be linked to adrenergic function.
4. Cardiac rhythm and Cardiac Failure: The β-AR signaling pathway serves as a primary component of the interface between the sympathetic nervous system and the cardiovascular system.^[10] The β-AR pathway dysregulation has been implicated in the pathogenesis of heart failure. It has been found that certain changes to β-AR signaling result in reduced levels of  β1-AR, by up to 50%, while levels of β2-AR remain constant. Other intracellular changes include a significant, sharp increase of GαI levels, and increased βARK1 activity. These changes suggest sharp decreases in  β-AR signaling, likely due to sustained, elevated levels of catecholamines.

Mechanism in cardiac myocytes

G_s 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. The phosphorylation of phospholamban deactivates its own function which normally inhibits 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 phosphorylation 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 speeds the muscle relaxation (positive lusitropy). Potassium channel phosphorylation 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.

Clinical Significance

Familial Natural Short Sleep (FNSS)

A rare mutation that changes a cytosine to a thymine in the ADRB-1 coding sequence results in a protein switch to valine from alanine at amino acid position 187 (A187) and leads to the FNSS behavior trait, where mutation carriers naturally wake up after only 4 to 6.5 hours of sleep. The ADRB-1 protein is involved in a cyclic adenosine monophosphate (cAMP)-mediated signaling pathway, and the ADRB1-A187V mutated protein leads to a lower cAMP production than the wild-type protein, given the same isoproterenol treatment, a nonselective agonist of ADRB-1. It was also discovered that the mutated protein is less stable most likely due to post-translational modifications, as shown in an ADRB1 knockin experiment where a mutated ADRB-1 gene replaces the wild-type with CRISPR technology and the protein level displays a decrease while the mRNA level remains high.^[11]

Mice with a heterozygous ADRB1-A187V mutation show increased activity time and shorter intervals of rapid eye movement (REM) sleep and non-REM sleep, suggesting that the mutation causes short sleep. In another experiment, the ADRB1-A187V mutation restored REM sleep in tau mice (PS19) and reduced tau accumulation, which can promote brain cell damage and death, in the locus coeruleus (LC) of PS19 mice.^[12] Furthermore, a high expression level of ADRB-1 protein is observed in the dorsal pons (DP), referred to as ADRB1+ neurons. The activity of these ADRB1+ neurons in DP is shown to be closely linked with the sleep-wake behavior and altered by the ADRB1-A187V mutation. The ADRB1+ neurons can be either inhibitory or excitatory. In the brains of mutant mice, the percentage of ADRB1+ neurons that may be inhibited by agonists reduces significantly while the percentage of neurons that may be excited by agonists remains relatively unchanged. It is thus speculated that the ADRB-1 protein has an inhibitory and an excitatory function, with the inhibitory function being more sensitive to its decreased protein levels and the excitatory function being less sensitive. Although the ADRB1-A187V mutation leads to lower protein levels, as discussed above, overall there are fewer ADRB1+ neurons inhibited, corresponding to the higher total activity of DP ADRB1+ neurons observed in mutant mice. These results collectively indicate that high activity levels in ADRB1+ neurons leads to shorter sleep or FNSS.

Polymorphisms in ADRB-1

One of the single nucleotide polymorphisms (SNPs) in ADRB-1 is the change from a cytosine to a guanine, resulting in a protein switch from arginine (389R) to glycine (389G) at the 389 codon position. Arginine at codon 389 is highly preserved across species and this mutation happens in the G-protein binding domain of ADRB-1, one of the key functions of ADRB-1 protein, so it is likely to lead to functional differences. In fact, this SNP causes dampened efficiency and affinity in agonist-promoted receptor binding.^[13]

Another common SNP occurs at codon position 49, with a change of serine (49S) to glycine (49G) in the N-terminus sequence of ADRB-1. The 49S variant is shown to be more resistant to agonist-promoted down regulation and short intervals of agonist exposure. The receptor of the 49G variant is always expressed, which results in high coupling activity with adenylyl cyclase and increased sensitivity to agonists.

Both of these SNPs have relatively high frequencies among populations and are thought to affect cardiac functions. Individuals who are homozygous for the 389R allele are more likely to have higher blood pressure and heart rates than others who have either one or two copies of the 389G allele. Additionally, patients with heart diseases that have a substitution of glycine for serine at codon 49 (49S > G) show improved cardiac functions and decreased mortality rate.^[14] The cardiovascular responses induced by this polymorphism in the healthy population are also examined. Healthy individuals with a glycine at codon 49 show better cardiovascular functions at rest and response to maximum heart rate during exercise, evident for the cardioprotection related to this polymorphism.

Pharmaceutical Interventions

Because ADRB-1 play such a critical role in maintaining blood pressure homeostasis and cardiac output, many medications treat these conditions by either potentiating or inhibiting the functions of the ADRB-1. Dobutamine is one of the adrenergic drugs and agonists that selectively bind to ADRB-1 and is often used in treatments of cardiogenic shock and heart failure.^[15] It is also important to note the use of illicit drug for ADRB-1 since cocaine, beta-blocking agents, or other sympathetic stimulators may cause a medical emergency.

Agonists

See main article: Beta1-adrenergic agonist.

ADRB-1 agonists mimic or initiate a physiological response when bound to a receptor. Isoprenaline has higher affinity for β₁ than adrenaline, which, in turn, binds with higher affinity than noradrenaline at physiologic concentrations. As ADRB-1 increases cardiac output, selective agonists clinically function as potential treatments for heart failure. Selective agonists to the beta-1 receptor are:

• Denopamine is used in the treatment of angina and has potential uses to treat congestive heart failure and pulmonary oedema.
• Dobutamine^[7] (in cardiogenic shock) is a beta-1 agonist that treats cardiac decompensation.
• Xamoterol^[7] (cardiac stimulant) acts as a partial agonist that improves heart function in studies with cardiac failure. Xamoterol plays a role in modulating the sympathetic nervous system, but does not have any agonistic action on beta-2 adrenergic receptors.
• Isoproterenol is a nonselective agonist that potentiates the effects of agents like adrenaline and norepinephrine to increase heart contractility.

Antagonists

ADRB-1 antagonists are a class of drugs also referred to as Beta Blockersβ1-selective antagonists are used to manage abnormal heart rhythms and block the action of substances like adrenaline on neurons, allowing blood to flow more easily which lowers blood pressure and cardiac output. They may also shrink vascular tumors. Some examples of Beta-Blockers include:

• Acebutolol (in hypertension, angina pectoris and arrhythmias)
• Atenolol^[7] (in hypertension, coronary heart disease, arrhythmias and myocardial infarction)
• Betaxolol (in hypertension and glaucoma)
• Bisoprolol^[16] (in hypertension, coronary heart disease, arrhythmias, myocardial infarction and ischemic heart diseases)
• Esmolol (in arrhythmias)
• Metoprolol^[7] (in hypertension, coronary heart disease, myocardial infarction and heart failure)
• Nebivolol (in hypertension)
• Vortioxetine (antidepressant)

See also

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

Further reading

• Frielle T, Kobilka B, Lefkowitz RJ, Caron MG . Human beta 1- and beta 2-adrenergic receptors: structurally and functionally related receptors derived from distinct genes . Trends in Neurosciences . 11 . 7 . 321–324 . July 1988 . 2465637 . 10.1016/0166-2236(88)90095-1 . 140209236 .
• Muszkat M . Interethnic differences in drug response: the contribution of genetic variability in beta adrenergic receptor and cytochrome P4502C9 . Clinical Pharmacology and Therapeutics . 82 . 2 . 215–218 . August 2007 . 17329986 . 10.1038/sj.clpt.6100142 . 10381767 .
• Yang-Feng TL, Xue FY, Zhong WW, Cotecchia S, Frielle T, Caron MG, Lefkowitz RJ, Francke U . Chromosomal organization of adrenergic receptor genes . Proceedings of the National Academy of Sciences of the United States of America . 87 . 4 . 1516–1520 . February 1990 . 2154750 . 53506 . 10.1073/pnas.87.4.1516 . free . 1990PNAS...87.1516Y .
• Forse RA, Leibel R, Gagner M . The effect of Escherichia coli endotoxin on the adrenergic control of lipolysis in the human adipocyte . The Journal of Surgical Research . 46 . 1 . 41–48 . January 1989 . 2536864 . 10.1016/0022-4804(89)90180-7 .
• Frielle T, Collins S, Daniel KW, Caron MG, Lefkowitz RJ, Kobilka BK . 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 . 7920–7924 . November 1987 . 2825170 . 299447 . 10.1073/pnas.84.22.7920 . free . 1987PNAS...84.7920F .
• Stiles GL, Strasser RH, Lavin TN, Jones LR, Caron MG, Lefkowitz RJ . 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 . 8443–8449 . July 1983 . 6305985 . 10.1016/S0021-9258(20)82084-5 . free .
• Hoehe MR, Otterud B, Hsieh WT, Martinez MM, Stauffer D, Holik J, Berrettini WH, Byerley WF, Gershon ES, Lalouel JM . Genetic mapping of adrenergic receptor genes in humans . Journal of Molecular Medicine . 73 . 6 . 299–306 . June 1995 . 7583452 . 10.1007/BF00231616 . 27308274 .
• Elies R, Ferrari I, Wallukat G, Lebesgue D, Chiale P, Elizari M, Rosenbaum M, Hoebeke J, Levin MJ . Structural and functional analysis of the B cell epitopes recognized by anti-receptor autoantibodies in patients with Chagas' disease . Journal of Immunology . 157 . 9 . 4203–4211 . November 1996 . 10.4049/jimmunol.157.9.4203 . 8892658 . 44386743 . free .
• Oldenhof J, Vickery R, Anafi M, Oak J, Ray A, Schoots O, Pawson T, von Zastrow M, Van Tol HH . SH3 binding domains in the dopamine D4 receptor . Biochemistry . 37 . 45 . 15726–15736 . November 1998 . 9843378 . 10.1021/bi981634+ .
• Mason DA, Moore JD, Green SA, Liggett SB . A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor . The Journal of Biological Chemistry . 274 . 18 . 12670–12674 . April 1999 . 10212248 . 10.1074/jbc.274.18.12670 . free .
• Moore JD, Mason DA, Green SA, Hsu J, Liggett SB . Racial differences in the frequencies of cardiac beta(1)-adrenergic receptor polymorphisms: analysis of c145A>G and c1165G>C . Human Mutation . 14 . 3 . 271 . September 1999 . 10477438 . 10.1002/(SICI)1098-1004(1999)14:3<271::AID-HUMU14>3.0.CO;2-Q . 8860722 .
• Tang Y, Hu LA, Miller WE, Ringstad N, Hall RA, Pitcher JA, DeCamilli P, Lefkowitz RJ . 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 . 12559–12564 . October 1999 . 10535961 . 22990 . 10.1073/pnas.96.22.12559 . free . 1999PNAS...9612559T .
• Podlowski S, Wenzel K, Luther HP, Müller J, Bramlage P, Baumann G, Felix SB, Speer A, Hetzer R, Köpke K, Hoehe MR, Wallukat G . Beta1-adrenoceptor gene variations: a role in idiopathic dilated cardiomyopathy? . Journal of Molecular Medicine . 78 . 2 . 87–93 . 2000 . 10794544 . 10.1007/s001090000080 . 1072602 .
• Shiina T, Kawasaki A, Nagao T, Kurose H . Interaction with beta-arrestin determines the difference in internalization behavor between beta1- and beta2-adrenergic receptors . The Journal of Biological Chemistry . 275 . 37 . 29082–29090 . September 2000 . 10862778 . 10.1074/jbc.M909757199 . free .
• Hu LA, Tang Y, Miller WE, Cong M, Lau AG, Lefkowitz RJ, Hall RA . 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 . 38659–38666 . December 2000 . 10995758 . 10.1074/jbc.M005938200 . free .
• Börjesson M, Magnusson Y, Hjalmarson A, Andersson B . 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 . 1853–1858 . November 2000 . 11052857 . 10.1053/euhj.1999.1994 . free .
• Xu J, Paquet M, Lau AG, Wood JD, Ross CA, Hall RA . 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 . 41310–41317 . November 2001 . 11526121 . 10.1074/jbc.M107480200 . free .
• Hu LA, Chen W, Premont RT, Cong M, Lefkowitz RJ . G protein-coupled receptor kinase 5 regulates beta 1-adrenergic receptor association with PSD-95 . The Journal of Biological Chemistry . 277 . 2 . 1607–1613 . January 2002 . 11700307 . 10.1074/jbc.M107297200 . free .
• 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 . A polymorphism in the beta1 adrenergic receptor is associated with resting heart rate . American Journal of Human Genetics . 70 . 4 . 935–942 . April 2002 . 11854867 . 379121 . 10.1086/339621 .

Further reading

• Book: Alhayek S, Preuss CV . Beta 1 Receptors. . August 2022 . StatPearls [Internet] . Treasure Island (FL) . StatPearls Publishing . https://www.ncbi.nlm.nih.gov/books/NBK532904/ . 30422499 .

External links

• • Web site: β₁-adrenoceptor . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-11-25 . 2015-06-06 . https://web.archive.org/web/20150606204105/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2187 . dead .

Notes and References

1. Web site: ADRB1 adrenoceptor beta 1 [Homo sapiens (human)] - Gene - NCBI].
2. Book: Boron WF, Boulpaep EL . Medical physiology : a cellular and molecular approach . 2012 . 978-1-4377-1753-2 . Updated second . Philadelphia, PA . Saunders/Elsevier . 756281854 .
3. Rosenbaum DM, Rasmussen SG, Kobilka BK . The structure and function of G-protein-coupled receptors . Nature . 459 . 7245 . 356–363 . May 2009 . 19458711 . 10.1038/nature08144 . 3967846 . 2009Natur.459..356R .
4. Nestler EJ, Duman RS . 1999 . Heterotrimeric G Proteins . Basic Neurochemistry: Molecular, Cellular and Medical Aspects . 6th . en.
5. Book: Fitzpatrick D, Purves D, Augustine G . Sinauer . 2004 . 978-0-87893-725-7 . Third . Sunderland, Mass . Neuroscience . Table 20:2 .
6. Moro C, Tajouri L, Chess-Williams R . Adrenoceptor function and expression in bladder urothelium and lamina propria . Urology . 81 . 1 . 211.e1–211.e7 . January 2013 . 23200975 . 10.1016/j.urology.2012.09.011 .
7. Book: Rang, H. P. . Pharmacology . Churchill Livingstone . 2003 . 978-0-443-07145-4 . Edinburgh. Page 163
8. Leach S, Suzuki K . Adrenergic Signaling in Circadian Control of Immunity . Frontiers in Immunology . 11 . 1235 . 2020 . 32714319 . 10.3389/fimmu.2020.01235 . 7344327 . free .
9. Jovanovic A, Xu B, Zhu C, Ren D, Wang H, Krause-Hauch M, Abel ED, Li J, Xiang YK . Characterizing Adrenergic Regulation of Glucose Transporter 4-Mediated Glucose Uptake and Metabolism in the Heart . JACC. Basic to Translational Science . 8 . 6 . 638–655 . June 2023 . 37426525 . 10322917 . 10.1016/j.jacbts.2022.11.008 .
10. Madamanchi A . Beta-adrenergic receptor signaling in cardiac function and heart failure . McGill Journal of Medicine . 10 . 2 . 99–104 . July 2007 . 18523538 . 2323471 .
11. Shi G, Xing L, Wu D, Bhattacharyya BJ, Jones CR, McMahon T, Chong SY, Chen JA, Coppola G, Geschwind D, Krystal A, Ptáček LJ, Fu YH . A Rare Mutation of β₁-Adrenergic Receptor Affects Sleep/Wake Behaviors . Neuron . 103 . 6 . 1044–1055.e7 . September 2019 . 31473062 . 6763376 . 10.1016/j.neuron.2019.07.026 .
12. Dong Q, Ptáček LJ, Fu YH . Mutant β₁-adrenergic receptor improves REM sleep and ameliorates tau accumulation in a mouse model of tauopathy . Proceedings of the National Academy of Sciences of the United States of America . 120 . 15 . e2221686120 . April 2023 . 37014857 . 10.1073/pnas.2221686120 . 257922859 . 10104526 . 2023PNAS..12021686D .
13. Sandilands AJ, O'Shaughnessy KM . The functional significance of genetic variation within the beta-adrenoceptor . British Journal of Clinical Pharmacology . 60 . 3 . 235–243 . September 2005 . 16120061 . 1884766 . 10.1111/j.1365-2125.2005.02438.x .
14. Kelley EF, Snyder EM, Johnson BD . Influence of Beta-1 Adrenergic Receptor Genotype on Cardiovascular Response to Exercise in Healthy Subjects . Cardiology Research . 9 . 6 . 343–349 . December 2018 . 30627284 . 6306116 . 10.14740/cr785 .
15. Book: Farzam K, Kidron A, Lakhkar AD . Adrenergic Drugs . 2023 . http://www.ncbi.nlm.nih.gov/books/NBK534230/ . StatPearls . 2023-04-26 . Treasure Island (FL) . StatPearls Publishing . 30480963 .
16. Web site: Bisoprolol . American Society of Health-System Pharmacists, Inc. . 2005-01-01 . MedlinePlus Drug Information . U.S. National Library of Medicine, National Institutes of Health . https://web.archive.org/web/20080520211346/http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a693024.html . 2008-05-20 . 2008-06-06 . dead .