Available structures
PDBOrtholog search: PDBe RCSB
AliasesADRB1, ADRB1R, B1AR, BETA1AR, RHR, adrenoceptor beta 1, FNSS2
External IDsOMIM: 109630 MGI: 87937 HomoloGene: 20171 GeneCards: ADRB1
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 10: 114.04 – 114.05 MbChr 19: 56.71 – 56.72 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

The beta-1 adrenergic receptor1 adrenoceptor), also known as ADRB1, can refer to either the protein-encoding gene (gene ADRB1) or one of the four adrenergic receptors.[5] 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


ADRB-1 is a transmembrane protein that belongs to the G-Protein-Coupled Receptor (GPCR) family.[6][7] 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.[8] 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).



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) [9]
Increases atrial contractility (inotropic effect) Cardiac muscle
Increases contractility and automaticity Ventricular cardiac muscle [9]
Increases conduction and automaticity Atrioventricular node (AV node)[9]
Relaxation Urinary bladder wall[10]
Exocrine Releases renin Juxtaglomerular cells.[9]
Stimulates viscous, amylase-filled secretions

Salivary glands[11]

Other Lipolysis Adipose tissue[9]

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.[12] 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.[13] 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.[12] 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.[14] 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

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. 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.[6]

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.[15] 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.[15]

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.[16] 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.[15] 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.[17]

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.[17]

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.[18] 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.[18]

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.[19] 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.


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:


ADRB-1 antagonists are a class of drugs also referred to as Beta Blockers β1-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:

See also


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000043591 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000035283 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: ADRB1 adrenergic, beta-1-, receptor".
  6. ^ a b Boron WF, Boulpaep EL (2012). Medical physiology : a cellular and molecular approach (Updated second ed.). Philadelphia, PA. ISBN 978-1-4377-1753-2. OCLC 756281854.((cite book)): CS1 maint: location missing publisher (link)
  7. ^ Rosenbaum DM, Rasmussen SG, Kobilka BK (May 2009). "The structure and function of G-protein-coupled receptors". Nature. 459 (7245): 356–363. Bibcode:2009Natur.459..356R. doi:10.1038/nature08144. PMC 3967846. PMID 19458711.
  8. ^ Nestler EJ, Duman RS (1999). "Heterotrimeric G Proteins". Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th Edition.
  9. ^ a b c d e Fitzpatrick D, Purves D, Augustine G (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 978-0-87893-725-7.
  10. ^ Moro C, Tajouri L, Chess-Williams R (January 2013). "Adrenoceptor function and expression in bladder urothelium and lamina propria". Urology. 81 (1): 211.e1–211.e7. doi:10.1016/j.urology.2012.09.011. PMID 23200975.
  11. ^ a b c d e Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 978-0-443-07145-4. Page 163
  12. ^ a b Leach S, Suzuki K (2020). "Adrenergic Signaling in Circadian Control of Immunity". Frontiers in Immunology. 11: 1235. doi:10.3389/fimmu.2020.01235. PMC 7344327. PMID 32714319.
  13. ^ Jovanovic A, Xu B, Zhu C, Ren D, Wang H, Krause-Hauch M, et al. (February 2023). "Characterizing Adrenergic Regulation of Glucose Transporter 4-Mediated Glucose Uptake and Metabolism in the Heart". JACC: Basic to Translational Science. 8 (6): 638–655. doi:10.1016/j.jacbts.2022.11.008. PMC 10322917. PMID 37426525.
  14. ^ Madamanchi A (July 2007). "Beta-adrenergic receptor signaling in cardiac function and heart failure". McGill Journal of Medicine. 10 (2): 99–104. PMC 2323471. PMID 18523538.
  15. ^ a b c Shi G, Xing L, Wu D, Bhattacharyya BJ, Jones CR, McMahon T, et al. (September 2019). "A Rare Mutation of β1-Adrenergic Receptor Affects Sleep/Wake Behaviors". Neuron. 103 (6): 1044–1055.e7. doi:10.1016/j.neuron.2019.07.026. PMC 6763376. PMID 31473062.
  16. ^ Dong Q, Ptáček LJ, Fu YH (April 2023). "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. Bibcode:2023PNAS..12021686D. doi:10.1073/pnas.2221686120. PMC 10104526. PMID 37014857. S2CID 257922859.
  17. ^ a b Sandilands AJ, O'Shaughnessy KM (September 2005). "The functional significance of genetic variation within the beta-adrenoceptor". British Journal of Clinical Pharmacology. 60 (3): 235–243. doi:10.1111/j.1365-2125.2005.02438.x. PMC 1884766. PMID 16120061.
  18. ^ a b Kelley EF, Snyder EM, Johnson BD (December 2018). "Influence of Beta-1 Adrenergic Receptor Genotype on Cardiovascular Response to Exercise in Healthy Subjects". Cardiology Research. 9 (6): 343–349. doi:10.14740/cr785. PMC 6306116. PMID 30627284.
  19. ^ Farzam K, Kidron A, Lakhkar AD (2023), "Adrenergic Drugs", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30480963, retrieved 2023-04-26
  20. ^ 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.

Further reading

Further reading