# Beta-1 adrenergic receptor
The beta-1 adrenergic receptor (β₁AR), encoded in humans by the gene [ADRB1](https://www.edgepedia.org/adrb1), is a [G protein-coupled receptor](https://www.edgepedia.org/g-protein-coupled-receptor) that binds the catecholamines epinephrine and norepinephrine and is the predominant beta-adrenergic receptor of the heart, where it mediates the increases in heart rate and contractility produced by sympathetic nervous system activation.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC11192237/) • [2](https://files.cpicpgx.org/data/guideline/publication/beta_blockers/2024/38951961.pdf) It is the main pharmacological target of beta-1 selective beta-blockers such as metoprolol and bisoprolol.[2](https://files.cpicpgx.org/data/guideline/publication/beta_blockers/2024/38951961.pdf)
| Key fact | Detail |
|---|---|
| Receptor class | Member of the beta-adrenergic receptors, G protein-coupled receptors targeted by catecholamines, especially adrenaline and noradrenaline[3](https://goldbook.iupac.org/terms/view/11570) |
| Subtype definition | β₁ and β₂ subtypes distinguished by Lands and colleagues in 1967; β₁ mainly cardiac (enhanced myocardial contractility), β₂ mainly bronchodilation and vasodilation[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC12830978/) |
| Gene | Human β₁AR cDNA of 2400 base pairs named ADRB1 (1987); gene localized to 10q24-q26 (1990), on the forward strand of chromosome 10 at 10q25.3[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC12830978/) • [5](https://pmc.ncbi.nlm.nih.gov/articles/PMC12030580/) |
| Signaling | Couples to the stimulatory Gs protein, raising cAMP and activating protein kinase A, which increases the L-type Ca²⁺ current through CaV1.2 channels[6](https://pubmed.ncbi.nlm.nih.gov/23948586/) |
| Structures | First protein structure solved for the turkey β₁AR in 2008; human β₁AR structure resolved in 2021[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC12830978/) |
| Blockade in heart failure | β₁-selective (bisoprolol, metoprolol CR/XL) and nonselective (carvedilol) blockers each produced a 34% reduction in all-cause mortality in large trials[7](https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/211340) |
| Key variants | ADRB1 rs1801252 (Ser49Gly) and rs1801253 (Gly389Arg) are the most extensively studied variants; Gly389 decreases G-protein coupling efficiency[2](https://files.cpicpgx.org/data/guideline/publication/beta_blockers/2024/38951961.pdf) |
## Discovery
The receptor concept emerged in the early 20th century: in 1905 [John Newport Langley](https://www.edgepedia.org/john-newport-langley) described an "accessory substance" on the cell membrane through which nicotine and curare acted on striated muscle, and in 1908 [Paul Ehrlich](https://www.edgepedia.org/paul-ehrlich) named the chemical groups in protoplasm that interact with drugs "receptors".[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC12830978/) In 1948 Raymond Parker Ahlquist provided the first confirmed evidence for adrenergic receptors and divided them into alpha and beta types.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC12830978/) James Whyte Black developed the first clinically applicable beta-blocker, propranolol, based on this theory in 1962.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC12830978/)
**Subtyping and cloning.** In 1967 Anthony M. Lands and colleagues subdivided the beta receptors into β₁ and β₂, associating β₁ with cardiac function and β₂ with bronchodilation and vasodilation.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC12830978/) In 1974 Bo Ablad proposed that both subtypes coexist in the human heart.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC12830978/) The cloning of the β₂ receptor revealed the seven-transmembrane architecture shared with rhodopsin, and the β₁AR, the predominant beta-adrenergic receptor in the heart, was subsequently cloned by a similar strategy; the human β₁ receptor was cloned by cross-hybridization with the 5HT1a receptor (Frielle et al., 1987).[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC11192237/) • [8](https://discovery.ucl.ac.uk/10111503/1/out.pdf) By 1987 the human β₁AR cDNA had been defined as 2400 base pairs and named ADRB1, and in 1990 the gene was mapped to chromosome 10q24-q26.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC12830978/)
**Structures.** The receptor's high activity and low stability delayed structural work until 2008, when researchers solved the first β₁AR protein structure, from the turkey.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC12830978/) With 64% sequence identity, the turkey β₁ receptor structure closely resembled the human β₂ receptor structure, the main difference being an α-helical element in the second extracellular loop of the former.[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC2801150/) The human β₁AR structure was resolved in 2021.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC12830978/)
## Signaling in the cardiomyocyte
Adrenergic stimulation activates β-adrenergic receptors coupled to the heterotrimeric stimulatory Gs protein, which activates adenylyl cyclase, raises cyclic AMP, and activates protein kinase A (PKA).[6](https://pubmed.ncbi.nlm.nih.gov/23948586/) A principal PKA target is the cardiac L-type Ca²⁺ channel CaV1.2, located in the plasma membrane and T-tubules, which mediates calcium entry into cardiomyocytes; β-adrenergic receptor activation increases this Ca²⁺ current and accounts for the positive inotropic effect of adrenergic stimulation.[6](https://pubmed.ncbi.nlm.nih.gov/23948586/) Sympathetic agonists acting through these pathways increase heart rate (chronotropy), contraction strength (inotropy), and relaxation rate (lusitropy), effects that correlate with increased intracellular calcium.[10](https://www.annualreviews.org/content/journals/10.1146/annurev-physiol-060121-041653)
Prolonged stimulation turns the receptor off. Sustained β₁ stimulation leads to desensitization and down-regulation, which plays a key role in the development and progression of cardiovascular disease.[2](https://files.cpicpgx.org/data/guideline/publication/beta_blockers/2024/38951961.pdf) Mechanistically, phosphorylation of the receptor by G protein-coupled receptor kinases and PKA recruits β-arrestin, which physically blocks further receptor-[G protein](https://www.edgepedia.org/g-protein) coupling and promotes endocytosis into endosomes.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC3266006/) β-arrestin also scaffolds signaling proteins, mediating EGFR transactivation and ERK activation.[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC6205195/)
## Role in heart failure
In chronic heart failure, sustained sympathetic drive chronically elevates norepinephrine and down-regulates β₁ receptors; chronic elevation of plasma norepinephrine is associated with poor prognosis.[7](https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/211340) Alterations in the failing heart include β₁ receptor down-regulation, uncoupling of stimulatory G proteins, and up-regulation of β-adrenoreceptor kinase with enhanced phosphorylation of β₁ and β₂ receptors.[7](https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/211340) β₁ receptors also appear central to norepinephrine-induced cardiomyocyte apoptosis, and in vitro β₁ antagonism inhibits apoptosis while β₂ antagonism increases it.[7](https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/211340)
Large randomized trials established the benefit of blocking this receptor. In CIBIS-II, bisoprolol reduced all-cause mortality by 34% (11.8% vs 17.3% deaths) in NYHA class III-IV patients, and MERIT-HF reported a 34% risk reduction for all-cause mortality with metoprolol CR/XL, including a 41% decrease in sudden death.[7](https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/211340) β₁-selective antagonists such as metoprolol and bisoprolol up-regulate cardiac β₁ receptors and restore responsiveness to catecholamines; in a direct comparison, metoprolol increased β-receptor density in endomyocardial membranes while carvedilol did not alter receptor number.[7](https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/211340)
## Beta-blockers and selectivity
Beta-blockers are classified as β₁-selective or nonselective by their relative ability to antagonize sympathomimetic amines in some tissues at lower doses than others. At low doses, β₁-selective drugs inhibit cardiac β₁ receptors with less effect on bronchial and vascular β₂ receptors; at higher doses they also block β₂ receptors.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC8109906/) This selectivity may be safer in bronchospastic disease and may avoid the pressor effect that nonselective blockers can produce during epinephrine infusion by removing β₂-mediated vasodilation.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC8109906/) [Practolol](https://www.edgepedia.org/practolol), introduced in 1970 as the first β₁-selective blocker, was withdrawn after causing oculomucocutaneous syndrome; later selective agents include metoprolol, atenolol, betaxolol, bisoprolol, esmolol, and [acebutolol](https://www.edgepedia.org/acebutolol).[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC8109906/)
Measured selectivity varies by assay. In recombinant cells expressing human receptors, bisoprolol showed the highest β₁ selectivity, with a β₂/β₁ affinity ratio of 19, while atenolol, metoprolol, and betaxolol were less selective and propranolol and carvedilol showed no significant selectivity.[14](https://pubmed.ncbi.nlm.nih.gov/10372227/) A whole-cell binding study across human β₁, β₂, and β₃ receptors found that the β₁/β₂ selectivity of most clinically used β-blockers is poor in intact cells, ranging from bisoprolol (14-fold β₁-selective) to timolol (26-fold β₂-selective).[15](https://pmc.ncbi.nlm.nih.gov/articles/PMC1576008/) In a volunteer study using exercise tachycardia as a β₁-mediated response, relative β₁-selectivity versus propranolol was 12.2 for bisoprolol, 9.0 for metoprolol, and 6.2 for acebutolol.[16](https://pubmed.ncbi.nlm.nih.gov/2439798/)
For hypertension, a Cochrane review of 56 trials in 7812 people found that β₁-selective blockers lowered blood pressure by an average of 10/8 mmHg and reduced heart rate by 11 beats per minute versus placebo in mild to moderate hypertension, judged low-quality evidence.[17](https://www.cochrane.org/CD007451/HTN_beta-1-selective-blockers-treatment-high-blood-pressure)
## Pharmacogenetics
The two most prevalent and well-studied ADRB1 variants are rs1801252 (Ser49Gly) and rs1801253 (Gly389Arg).[18](https://www.nature.com/articles/s41525-025-00511-6) The Gly49 allele increases agonist-promoted desensitization, and Gly389 decreases the efficiency of G-protein coupling; both reduce adenylyl cyclase activity and cAMP production.[2](https://files.cpicpgx.org/data/guideline/publication/beta_blockers/2024/38951961.pdf) The Arg389 variant sits in the cytoplasmic tail critical for G-protein interaction, and the C allele (Arg) reaches frequencies of 80.5% in American and 68.5% in European populations.[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC12030580/) The strongest pharmacogenetic evidence links ADRB1 genotype to reduced diastolic blood pressure response to β-blockers, with no association with heart rate or systolic blood pressure changes.[18](https://www.nature.com/articles/s41525-025-00511-6) The 2024 CPIC guideline, however, found insufficient evidence to make therapeutic recommendations for any beta-blocker based on ADRB1 or the other pharmacodynamic genes evaluated.[2](https://files.cpicpgx.org/data/guideline/publication/beta_blockers/2024/38951961.pdf)
Beyond the cardiovascular system, β₁ receptors participate in brain functions including sleep and wakefulness, memory, and stress responses; the naturally occurring Adrb1^A187V variant is linked to short sleep in humans and mice.[19](https://www.nature.com/articles/s41467-025-65964-w)
## References
1. [G Protein-Coupled Receptors: A Century of Research and Discovery, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC11192237/)
2. [CPIC Guideline for CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4, and GRK5 Genotypes and Beta-Blocker Therapy (2024)](https://files.cpicpgx.org/data/guideline/publication/beta_blockers/2024/38951961.pdf)
3. [β-adrenergic receptor, IUPAC Compendium of Chemical Terminology](https://goldbook.iupac.org/terms/view/11570)
4. [The beta1-adrenergic receptor in the heart, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC12830978/)
5. [Impact of Genetic Variation in Adrenergic Receptors on β-Blocker Effectiveness and Safety, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC12030580/)
6. [Regulation of cardiac L-type Ca²⁺ channel CaV1.2 via the β-adrenergic-cAMP-PKA pathway, PubMed](https://pubmed.ncbi.nlm.nih.gov/23948586/)
7. [Goldstein S. Benefits of β-Blocker Therapy for Heart Failure, Arch Intern Med 2002](https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/211340)
8. [The cloning of the beta 2 adrenergic receptor gene, UCL Discovery](https://discovery.ucl.ac.uk/10111503/1/out.pdf)
9. [Rhodopsin and the others: a historical perspective on structural studies of GPCRs, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC2801150/)
10. [Papa, Kushner, Marx. Adrenergic Regulation of Calcium Channels in the Heart, Annual Review of Physiology 2022](https://www.annualreviews.org/content/journals/10.1146/annurev-physiol-060121-041653)
11. [Regulation of β-adrenergic receptor function: an emphasis on receptor resensitization, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3266006/)
12. [G protein-coupled receptors in heart disease, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC6205195/)
13. [A Historical Perspective on the Development of β-Adrenergic Blockers, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC8109906/)
14. [Beta-blocker selectivity at cloned human beta 1- and beta 2-adrenergic receptors, PubMed](https://pubmed.ncbi.nlm.nih.gov/10372227/)
15. [The selectivity of β-adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC1576008/)
16. [Comparison of bisoprolol with other beta-adrenoceptor blocking drugs, PubMed](https://pubmed.ncbi.nlm.nih.gov/2439798/)
17. [Beta-1 selective blockers for treatment of high blood pressure, Cochrane](https://www.cochrane.org/CD007451/HTN_beta-1-selective-blockers-treatment-high-blood-pressure)
18. [Pharmacogenetics of cardiovascular disease and impact on clinical implications, npj Genomic Medicine](https://www.nature.com/articles/s41525-025-00511-6)
19. [Prime editing of the β1 adrenoceptor in the brain restores physiological REM sleep, Nature Communications](https://www.nature.com/articles/s41467-025-65964-w)
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*Topic: Encyclopedia › Life and health › Human health and medicine › Human structure and function › Cardiovascular and lymphatic systems › Heart › Cardiac physiology and hemodynamics › Heart rate and its regulation › Autonomic control of heart rate*
*Initially written Sep 17, 2026 · Reviewed: Sep 30, 2026; Oct 21, 2026 · Edited: Sep 30, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
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License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license