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Beta-1 adrenergic receptor
Beta-1 adrenergic receptor
Beta-1 adrenergic receptor
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"B1 receptor" redirects here. For the bradykinin receptor, see Bradykinin receptor B1.

ADRB1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesADRB1, ADRB1R, B1AR, BETA1AR, RHR, adrenoceptor beta 1, FNSS2
External IDsOMIM: 109630; MGI: 87937; HomoloGene: 20171; GeneCards: ADRB1; OMA:ADRB1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

153

11554

Ensembl

ENSG00000043591

ENSMUSG00000035283

UniProt

P08588

P34971

RefSeq (mRNA)

NM_000684

NM_007419

RefSeq (protein)

NP_000675

NP_031445

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

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.[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

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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

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Structure

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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).

Function

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Pathways

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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.[9]

Summary of interactions

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Actions of the β1 receptor include:

System Effect Tissue
Muscular Increases cardiac output Cardiac muscle
Increases heart rate (chronotropic effect) Sinoatrial node (SA node) [10]
Increases atrial contractility (inotropic effect) Cardiac muscle
Increases contractility and automaticity Ventricular cardiac muscle [10]
Increases conduction and automaticity Atrioventricular node (AV node)[10]
Relaxation Urinary bladder wall[11]
Exocrine Releases renin Juxtaglomerular cells.[10]
Stimulates viscous, amylase-filled secretions

Salivary glands[12]

Other Lipolysis Adipose tissue[10]

The receptor is also present in the cerebral cortex.

Other pathways that the 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.[13] 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.[14] 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.[13] 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.[15] 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

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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. 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

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Familial natural short sleep (FNSS)

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A missense variant in the ADRB-1 coding sequence was initially identified as causing familial natural short sleep[16] in one affected family. However, subsequent biobank research showed that other carriers of this mutation or of different high-impact mutations in the same gene did not exhibit any change in sleep duration, indicating that the cause of the short sleeper phenotype in this family had a different basis.[17]

Polymorphisms

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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.[18]

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.[18]

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.[19] 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.[19]

Pharmaceutical interventions

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Because ADRB-1 plays 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.[20] 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

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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[12] (in cardiogenic shock) is a beta-1 agonist that treats cardiac decompensation.
  • Xamoterol[12] (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

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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

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References

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Further reading

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Beta-1 adrenergic receptor

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from Grokipedia
The β₁-adrenergic receptor (β₁-AR), also known as ADRB1, is a subtype of the family and a member of the (GPCR) superfamily, primarily responsible for mediating the physiological effects of catecholamines such as norepinephrine and epinephrine in the . It is characterized by a seven-transmembrane α-helical structure, with an extracellular , an intracellular , and ligand-binding pocket formed by transmembrane helices TM3, TM5, TM6, and TM7, as revealed by crystal structures such as the 2.7 Å resolution structure of the turkey β₁-AR (PDB: 2VT4, sharing 82% sequence identity with human) and more recent human β₁-AR structures (e.g., PDB: 7BU6). More recent cryo-EM structures, including full-length human β₁-AR (e.g., PDB: 8S2T, 2025), have further elucidated interactions. Functionally, the β₁-AR couples predominantly to the stimulatory (Gₛ) subunit, activating to increase intracellular (cAMP) levels, which in turn activates (PKA) and modulates ion channels and contractile proteins to enhance cellular responses. In the heart, where it is most abundantly expressed, β₁-AR stimulation increases (positive chronotropy), (positive inotropy), and conduction velocity (positive dromotropy), thereby boosting during the "fight or flight" response; it is also present in renal juxtaglomerular cells, promoting renin release to regulate , and in adipocytes, facilitating . The receptor exhibits high affinity for both epinephrine and norepinephrine, with a (K_d) in the micromolar range, and its activation can lead to downstream effects including elevated intracellular calcium via PKA of L-type calcium channels. Pharmacologically, β₁-AR serves as a key target for therapeutic interventions, with selective agonists like used to treat acute and by augmenting cardiac performance, while non-selective antagonists such as and cardioselective ones like atenolol or metoprolol are employed to manage , , arrhythmias, and chronic by blocking excessive sympathetic stimulation. Dysregulation of β₁-AR signaling, such as desensitization or downregulation in chronic , contributes to disease progression, and its overstimulation—e.g., in toxicity—can precipitate life-threatening . Ongoing research highlights the receptor's structural features, including the role of extracellular loop 2 (EL2) in binding stabilization via bonds and sodium coordination, informing the development of more precise allosteric modulators.

History and Discovery

Early Identification

The discovery of the beta-1 adrenergic receptor (β1-AR) began with foundational pharmacological classifications in the mid-20th century. In 1948, Raymond Ahlquist analyzed the relative potencies of catecholamines such as epinephrine, norepinephrine, and isoproterenol on various tissues, proposing the existence of two distinct subtypes: alpha (α-AR) and beta (β-AR). Ahlquist's work demonstrated that beta receptors mediated inhibitory responses in certain smooth muscles and excitatory effects in cardiac tissue, based on the consistent rank-order potency of agonists across these systems, laying the groundwork for subtype differentiation. By the , further pharmacological studies refined the beta receptor classification into β1 and β2 subtypes, primarily through comparative potency series of sympathomimetic amines in different tissues. A. M. Lands and colleagues in used agonists like isoproterenol (a potent non-selective β-agonist) and norepinephrine to show that cardiac responses followed a potency order distinct from those in bronchial or vascular , indicating β1-AR predominance in the heart and β2-AR in other sites. The introduction of antagonists such as , a non-selective β-blocker developed in the early 1960s, provided additional evidence by competitively inhibiting these responses with similar selectivity patterns, confirming the pharmacological separation of β1 from β2 receptors. In the early 1970s, radioligand binding techniques offered direct biochemical confirmation of the β1-AR as a distinct entity in cardiac tissue. Pioneering studies in 1974 employed tritiated antagonists like [³H]alprenolol to quantify high-affinity binding sites in myocardial membranes, revealing saturable, stereospecific interactions characteristic of β-adrenergic receptors and enriched in heart compared to tissues dominated by β2-AR. These assays demonstrated that cardiac binding sites exhibited pharmacological profiles matching β1 selectivity, such as greater affinity for norepinephrine over epinephrine, solidifying the receptor's identity and tissue specificity. The molecular era began in 1987 with the of the ADRB1 gene, which encodes the β1-AR. Using a placental cDNA library screened with a genomic probe, Frielle and colleagues isolated the full-length cDNA, revealing a 2.4-kilobase sequence predicting a 477-amino-acid protein with seven transmembrane domains typical of G-protein-coupled receptors (GPCRs). This identification linked the β1-AR to the emerging GPCR superfamily, enabling subsequent structural and functional analyses.

Key Milestones in Research

In the , researchers faced significant challenges in obtaining high-resolution structures of G protein-coupled receptors (GPCRs) like the beta-1 adrenergic receptor (β1AR) due to their inherent flexibility and membrane-embedded nature, leading to reliance on computational . These early models were constructed by threading the β1AR sequence onto the known topology of , a prototypical GPCR with low sequence identity but conserved seven-transmembrane helix architecture, to predict ligand-binding pockets and signaling interfaces. Such models provided initial insights into receptor conformation but were limited by the absence of atomic-level data, highlighting the need for experimental structures to refine understanding of β1AR activation. The foundational work on β-adrenergic receptors, including radioligand binding, earned Robert J. Lefkowitz the 2012 (shared with Brian K. Kobilka for GPCR studies), recognizing its impact on GPCR . A major breakthrough occurred in 2008 with the determination of the first of the β1AR at 2.7 resolution, stabilized with the cyanopindolol, which confirmed the seven-transmembrane helical bundle and identified key residues in the orthosteric , such as Asp121 and Asn329, critical for recognition. This structure, reported by Warne et al., overcame prior crystallization hurdles through thermostabilization mutations and lipidic cubic phase methods, serving as a foundational template for subsequent GPCR . Concurrently, genetic studies advanced with the identification of common ADRB1 polymorphisms, including Arg389Gly, in 1999, which alters receptor desensitization and coupling efficiency; the Arg389 variant was later associated with enhanced responses to beta-blockers in patients, influencing personalized . Advancements in the shifted toward dynamic states with cryo-electron microscopy (cryo-EM) structures of the human β1AR in complex with Gs heterotrimer and agonists like isoproterenol, resolved at resolutions around 3.2 , revealing conformational changes in transmembrane helices 5 and 6 that facilitate G-protein coupling and exchange. These structures, such as the 2020 β1AR-Gs complex, elucidated how intracellular loop 2 and helix 8 interactions stabilize the active conformation, providing mechanistic details absent in static crystal structures. More recently, from 2020 to 2025, research has focused on biased agonism and allosteric modulation to exploit pathway selectivity for cardioprotection; for instance, β--biased allosteric modulators like compound-6 enhance carvedilol's protective effects in cardiomyocytes by promoting β- recruitment over Gs signaling, reducing without compromising contractility. Similarly, studies on carvedilol's intrinsic bias at β1AR have highlighted conformational exclusion mechanisms that favor pathways, opening avenues for safer therapies.

Molecular Structure

Gene and Expression

The human ADRB1 gene, which encodes the beta-1 adrenergic receptor, is located on the long arm of chromosome 10 at position 10q25.3. It spans approximately 3 kilobases and consists of a single , producing a primary transcript that translates into a 477-amino-acid protein. ADRB1 is predominantly expressed in the heart, where it accounts for 70-80% of total beta-adrenergic receptors in nonfailing ventricular tissue, playing a central role in cardiac contractility. Lower expression levels are observed in other tissues, including the (involved in renin release), (lipolysis regulation), and (neuronal signaling). Alternative splicing of ADRB1 is limited in humans, with only one major transcript reported, but variants have been identified in rodents that influence receptor trafficking and membrane localization. The ADRB1 gene exhibits strong evolutionary conservation across mammals, with the protein sharing over 90% sequence identity with orthologs in rodents such as mouse (Adrb1) and rat (Adrb1), reflecting its essential role in sympathetic nervous system function. This high conservation underscores the reliability of rodent models for studying human beta-1 adrenergic receptor biology.

Protein Architecture and Binding Sites

The β1-adrenergic receptor (β1AR), encoded by the ADRB1 gene, belongs to the class A subfamily of G protein-coupled receptors (GPCRs) and exhibits the canonical architecture of seven transmembrane α-helices (TM1–TM7) arranged in a bundle, connected by three extracellular loops (ECL1–ECL3) and three intracellular loops (ICL1–ICL3), with an extracellular N-terminal domain and an intracellular C-terminal tail. This 7-transmembrane (7TM) topology positions the ligand-binding site within the helical bundle, while the intracellular regions facilitate interactions with G proteins and regulatory proteins. The orthosteric binding pocket, which accommodates endogenous catecholamines such as norepinephrine and epinephrine, is primarily formed by residues from TM3, TM5, TM6, and TM7, as revealed by high-resolution crystal structures. A key interaction involves the conserved residue Asp^{3.32} (Asp113 in human β1AR numbering) in TM3, which forms a with the protonated group of catecholamines, essential for high-affinity binding of both and antagonists. Additionally, serine residues in TM5, notably Ser^{5.42} (Ser211), contribute to efficacy by forming bonds with the catechol hydroxyl groups, influencing receptor and signaling . Intracellular loops ICL2 and ICL3 play critical roles in coupling, with ICL2 interacting directly with the α5 helix of the Gα subunit to stabilize the active conformation, while ICL3 provides flexibility for effector engagement. The C-terminal tail contains multiple phosphorylation sites that mediate desensitization and are targeted by (PKA) following agonist-induced , leading to of β-arrestins and of signaling. Upon binding, β1AR undergoes significant conformational changes, most prominently an outward tilt and rotation of the intracellular end of TM6 by approximately 14 Å relative to the inactive state, creating a binding interface for the Gs heterotrimer and enabling exchange on Gαs. This TM6 movement, conserved across class A GPCRs, is accompanied by subtle inward shifts in TM5 and TM7, optimizing the cytoplasmic crevice for docking. Recent cryo-EM and crystal structures have identified allosteric sites on β1AR, including cholesterol-binding pockets in the transmembrane region that modulate receptor function; cholesterol occupancy at these sites acts as a negative by restricting TM dynamics and reducing affinity. For instance, wedged between TM helices stabilizes an inactive-like conformation, highlighting modulation as a regulatory mechanism distinct from orthosteric interactions. A 2025 cryo-EM structure of the full-length human β1AR in complex with Gs heterotrimer (resolution ~3.2 Å) highlights the role of ICL3 in stabilizing interactions and enhancing cAMP signaling.

Physiological Function

Signaling Pathways

The β1-adrenergic receptor (β1AR) primarily couples to the stimulatory (Gs), composed of Gαs, Gβ, and Gγ subunits, upon binding such as norepinephrine or epinephrine. This interaction promotes the exchange of GDP for GTP on the Gαs subunit, leading to dissociation of the Gαs-GTP from the Gβγ complex. The free Gαs-GTP then activates (AC), an enzyme embedded in the plasma membrane. In cardiac myocytes, β1AR stimulation typically engages AC types V and VI, which are predominant isoforms in the heart. Adenylyl cyclase catalyzes the conversion of ATP to cyclic adenosine monophosphate (cAMP) and pyrophosphate (PPi), markedly elevating intracellular cAMP levels—often by 10- to 50-fold in response to agonist stimulation in cardiomyocytes. ATP→cAMP+PPi\text{ATP} \rightarrow \text{cAMP} + \text{PP}_\text{i} This second messenger then binds to the regulatory subunits of protein kinase A (PKA), a tetrameric holoenzyme, releasing the active catalytic subunits. Activated PKA phosphorylates key targets, including phospholamban (which relieves inhibition of the sarcoplasmic reticulum Ca²⁺-ATPase, enhancing Ca²⁺ uptake) and L-type voltage-gated Ca²⁺ channels (increasing Ca²⁺ influx during action potentials). These phosphorylation events amplify contractility and relaxation dynamics without directly specifying organ-level effects. In addition to canonical G protein signaling, prolonged β1AR activation recruits β-arrestins (primarily β-arrestin 2) to the phosphorylated receptor via kinases (GRKs), promoting desensitization by uncoupling the receptor from Gs and facilitating internalization. β-Arrestins also scaffold alternative signaling pathways, such as of the (EGFR), leading to ()/extracellular signal-regulated kinase (ERK) activation for sustained, G protein-independent responses. Furthermore, β-arrestin-mediated β1AR signaling engages ()/Akt pathways, providing cardioprotective effects like reduced and improved survival under stress, independent of Gs coupling.

Roles in Target Tissues

The β1-adrenergic receptor (β1-AR) plays a central role in mediating responses in key target tissues, particularly during stress and the fight-or-flight reaction, where it enhances cardiovascular performance, regulates , and mobilizes stores. , β1-ARs are densely expressed, with receptor densities typically ranging from 50 to 100 fmol/mg protein, and sympathetic innervation is highest here compared to other organs, enabling rapid adaptations to physiological demands. In cardiac myocytes, activation of β1-ARs promotes positive inotropy by increasing contractility through (PKA)-mediated phosphorylation of troponin I and myosin binding protein C, which accelerates cross-bridge cycling and enhances force generation. Additionally, β1-AR stimulation induces positive chronotropy by augmenting pacemaker activity in the sinoatrial (SA) node, thereby elevating to meet increased oxygen demands. These effects collectively boost during acute stress. In the kidneys, β1-ARs on juxtaglomerular cells trigger renin release upon sympathetic activation, which initiates the renin-angiotensin-aldosterone system (RAAS) to elevate and maintain fluid-electrolyte balance. This mechanism is crucial for sustaining during or exercise. In adipocytes, β1-AR activation stimulates by PKA and activation of hormone-sensitive lipase, breaking down triglycerides into free fatty acids and for energy mobilization during prolonged stress or . β1-ARs also exert minor roles in the , where they contribute to norepinephrine-mediated arousal and attention via noradrenergic projections, and in vascular , though β2-ARs predominate in mediating .

Pharmacology and Ligands

Endogenous and Natural Ligands

The primary endogenous ligands for the β₁-adrenergic receptor are the catecholamines norepinephrine and epinephrine, which serve as neurotransmitters and hormones in the . Norepinephrine, synthesized and released from postganglionic sympathetic neurons, binds to β₁ receptors with high affinity (Ki ≈ 300–1,000 nM). Epinephrine, produced in the and released into circulation, exhibits comparable binding affinity (Ki ≈ 500–1,000 nM) and contributes to systemic activation of β₁ receptors during stress. These ligands are biosynthesized from the in a stepwise pathway conserved across catecholaminergic cells. is first converted to L-3,4-dihydroxyphenylalanine () by the rate-limiting enzyme , followed by to via . is then hydroxylated to norepinephrine by dopamine β-hydroxylase, an enzyme localized within vesicles. In chromaffin cells of the , norepinephrine is further N-methylated to epinephrine by phenylethanolamine N-methyltransferase (PNMT), using S-adenosylmethionine as a methyl donor. This pathway ensures localized production of norepinephrine in sympathetic nerves and epinephrine primarily in the . The β₁ receptor displays a distinct selectivity profile among adrenergic receptors, favoring norepinephrine as its primary with approximately 10-fold higher affinity than at β₂ receptors, while affinities for epinephrine are similar across β subtypes. In contrast to α-adrenergic receptors, β₁ shows negligible binding affinity for these catecholamines at α sites. Compared to the synthetic isoproterenol, β₁ receptors exhibit relatively lower by norepinephrine than β₂ receptors do, underscoring subtype-specific physiological tuning. Dopamine, an upstream intermediate in catecholamine , acts as a weak at β₁ receptors only at elevated concentrations (≈10 μM), reflecting its low affinity (Ki >10 μM) and primary role at receptors. No endogenous antagonists of the β₁ receptor have been identified, allowing unopposed by catecholamines under physiological conditions. During acute stress or sympathetic activation, synaptic norepinephrine concentrations transiently peak at 10–100 μM in the cleft, enabling robust receptor saturation and downstream signaling.

Synthetic Agonists and Antagonists

Synthetic agonists of the β1-adrenergic receptor include , a catecholamine analog that exhibits selectivity for β1 over β2 and β3 receptors, with a pEC50 of 6.81 ( ≈ 155 nM) at human β1 receptors and an intrinsic approaching full agonism (97% of maximal response). Prenalterol serves as a at β1 receptors, eliciting submaximal responses compared to full agonists like , with reduced cardiostimulatory effects relative to due to its lower intrinsic . These agonists stabilize the active receptor conformation, promoting G-protein coupling and downstream signaling, though partial agonists like prenalterol achieve this with lower through incomplete stabilization of the active state. Synthetic antagonists, primarily β-blockers, competitively bind to the orthosteric site of the β1 receptor, preventing access and inhibiting receptor activation. Metoprolol is a β1-selective with a Ki of approximately 50 nM at β1 receptors and exhibits over 100-fold selectivity for β1 over β2 receptors, as determined in functional assays. Atenolol, another cardioselective , binds with high affinity to β1 receptors (Ki ≈ 40-60 nM) and lacks intrinsic sympathomimetic activity, distinguishing it from partial . In constitutively active β1 receptor mutants, like metoprolol and atenolol demonstrate inverse agonism by stabilizing the inactive receptor state and reducing basal activity. Pharmacokinetic properties support chronic oral administration of these antagonists; for instance, bisoprolol offers high (≈80%) and an elimination of approximately 10 hours, enabling once-daily dosing. Metoprolol, while also suitable for oral use, has a shorter of 3-7 hours and of about 50%, often requiring twice-daily dosing in immediate-release formulations.

Clinical Significance

Genetic Variations and Polymorphisms

The β1-adrenergic receptor is encoded by the ADRB1 gene on chromosome 10q25.3, where several common single nucleotide polymorphisms (SNPs) influence receptor function and have varying population frequencies. Two prominent SNPs are rs1801252 (Ser49Gly) and rs1801253 (Arg389Gly). The Ser49Gly polymorphism substitutes serine with glycine at position 49 in the receptor's N-terminal region, with the minor Gly49 allele occurring at a frequency of 12-16% in Caucasian populations. The Arg389Gly polymorphism replaces arginine with glycine at position 389 in the G-protein coupling domain, with the minor Gly389 allele frequency approximately 29% in Caucasians and higher at 42% in African Americans. Functionally, the Ser49 variant demonstrates reduced agonist-induced desensitization compared to Gly49, resulting in enhanced downstream signaling and greater cAMP production in response to isoproterenol stimulation in recombinant systems. In contrast, the Gly389 variant exhibits impaired coupling to Gs proteins, leading to diminished activation, reduced inotropic responses, and lower contractility in cellular and animal models. These effects contribute to variable cardiovascular phenotypes, with the Ser49 allele associated with increased risk of in some clinical cohorts. Population differences in allele frequencies impact pharmacogenomic responses; the elevated Gly389 frequency in correlates with attenuated β-blocker efficacy, such as reduced control during exercise with atenolol, independent of alone. Rare in ADRB1 also alter receptor function, including variants that decrease receptor stability and cAMP signaling but promote via enhanced in dorsal pons neurons, linking it to . For instance, a rare A187V substitution (p.Ala187Val) in the .

Therapeutic Applications and Interventions

Beta-1 adrenergic receptor antagonists, commonly known as beta-blockers, play a central role in managing by counteracting chronic sympathetic overactivation, which promotes myocardial remodeling and . In the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) , , a non-selective beta-blocker with alpha-1 blocking properties, reduced all-cause mortality by 35% in patients with severe chronic ( <25%), primarily through anti-remodeling effects that improved left ventricular function and reduced hospitalizations. Similarly, the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) demonstrated that the cardioselective beta-1 antagonist metoprolol succinate lowered mortality by 34% in symptomatic patients, highlighting the benefits of beta-1 blockade in stabilizing cardiac . In , cardioselective beta-1 antagonists like are preferred for their efficacy and tolerability profile. Clinical trials have shown reduces systolic by approximately 10-15 mmHg and diastolic by 8-10 mmHg in patients with stage 1 or 2 , with vasodilatory effects via release contributing to fewer adverse events compared to non-selective agents. This selectivity minimizes interference with beta-2 mediated bronchodilation, allowing safer use in comorbid conditions. For arrhythmias, particularly supraventricular tachycardia, ultra-short-acting beta-1 selective antagonists such as esmolol provide acute rate control without prolonged effects. Administered intravenously, esmolol achieves heart rate reduction in 85% of cases within 15 minutes at doses of 50-200 mcg/kg/min, making it ideal for perioperative or emergency settings where rapid onset and offset are critical. Emerging therapies target beta-1 receptor signaling to enhance heart failure treatment while avoiding traditional beta-blocker side effects like bradycardia. Preclinical studies in the 2020s have explored gene therapy delivering beta-adrenergic receptor kinase-1 inhibitors (βARKct) to inhibit desensitization of beta-1 receptors, restoring contractile function in animal models of heart failure without global adrenergic suppression. Additionally, biased agonists that preferentially activate G-protein pathways over β-arrestin-mediated ones are under investigation, potentially improving inotropy in heart failure while minimizing chronotropic effects and arrhythmias. Adverse effects of beta-1 antagonists include risk in asthmatic patients due to partial beta-2 , though cardioselective agents like metoprolol or are associated with lower risk compared to non-selective options, allowing cautious use with monitoring. Recent pharmacogenomic insights into beta-1 receptor polymorphisms (e.g., Arg389 ) guide personalized dosing to optimize outcomes in .

References

  1. https://www.ncbi.nlm.nih.gov/books/NBK532904/
  2. https://pmc.ncbi.nlm.nih.gov/articles/PMC2923055/
  3. https://www.rcsb.org/structure/7BU6
  4. https://www.rcsb.org/structure/8S2T
  5. https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=505
  6. https://journals.physiology.org/doi/full/10.1152/ajplegacy.1948.153.3.586
  7. https://www.nature.com/articles/214597a0
  8. https://pmc.ncbi.nlm.nih.gov/articles/PMC2801150/
  9. https://www.nobelprize.org/prizes/chemistry/2012/summary/
  10. https://www.nature.com/articles/nature07081
  11. https://www.sciencedirect.com/science/article/pii/S109727652030544X
  12. https://pubmed.ncbi.nlm.nih.gov/34561298/
  13. https://www.biorxiv.org/content/10.1101/2024.07.19.604263v1
  14. https://www.ncbi.nlm.nih.gov/gene/153
  15. https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000043591
  16. https://pubmed.ncbi.nlm.nih.gov/2876788/
  17. https://www.sciencedirect.com/topics/medicine-and-dentistry/beta-1-adrenergic-receptor
  18. https://www.uniprot.org/uniprotkb/P08588/entry
  19. https://pubmed.ncbi.nlm.nih.gov/2899076/
  20. https://www.nature.com/articles/s41467-022-31823-1
  21. https://pmc.ncbi.nlm.nih.gov/articles/PMC7541785/
  22. https://www.biorxiv.org/content/10.1101/2021.08.30.457941v1.full-text
  23. https://www.cell.com/structure/fulltext/S0969-2126(25)00268-0
  24. https://www.ahajournals.org/doi/10.1161/circresaha.110.231340
  25. https://www.pnas.org/doi/10.1073/pnas.95.3.1038
  26. https://www.ahajournals.org/doi/10.1161/circresaha.107.167817
  27. https://www.pnas.org/doi/10.1073/pnas.262789099
  28. https://www.jci.org/articles/view/31901
  29. https://www.sciencedirect.com/topics/neuroscience/beta-adrenergic-receptor
  30. https://pubmed.ncbi.nlm.nih.gov/22286918/
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC4930068/
  32. https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.313417
  33. https://www.biorxiv.org/content/10.1101/2022.07.13.499965v3.full-text
  34. https://www.ncbi.nlm.nih.gov/books/NBK470410/
  35. https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.2019.33.1_supplement.819.5
  36. https://pubmed.ncbi.nlm.nih.gov/17711991/
  37. https://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=4
  38. https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=28
  39. https://www.ncbi.nlm.nih.gov/books/NBK27988/
  40. https://www.ahajournals.org/doi/10.1161/01.cir.17.3.366
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC8089101/
  42. https://www.ncbi.nlm.nih.gov/books/NBK540977/
  43. https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2010.00754.x
  44. https://pubmed.ncbi.nlm.nih.gov/2859252/
  45. https://www.sciencedirect.com/science/article/pii/S0022356525218687
  46. https://pmc.ncbi.nlm.nih.gov/articles/PMC6165953/
  47. https://www.tandfonline.com/doi/full/10.1080/03007995.2024.2317433
  48. https://www.ncbi.nlm.nih.gov/books/NBK499982/
  49. https://pubmed.ncbi.nlm.nih.gov/17031074/
  50. https://www.ncbi.nlm.nih.gov/books/NBK551623/
  51. https://go.drugbank.com/drugs/DB00264
  52. https://pmc.ncbi.nlm.nih.gov/articles/PMC3245828/
  53. https://pmc.ncbi.nlm.nih.gov/articles/PMC2757009/
  54. https://pmc.ncbi.nlm.nih.gov/articles/PMC3919627/
  55. https://pubmed.ncbi.nlm.nih.gov/19743955/
  56. https://pmc.ncbi.nlm.nih.gov/articles/PMC6763376/
  57. https://www.nejm.org/doi/full/10.1056/NEJM200105313442201
  58. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)04440-2/fulltext
  59. https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2020.613917/full
  60. https://pubmed.ncbi.nlm.nih.gov/2899451/
  61. https://pmc.ncbi.nlm.nih.gov/articles/PMC2570774/
  62. https://pmc.ncbi.nlm.nih.gov/articles/PMC7878421/
  63. https://pmc.ncbi.nlm.nih.gov/articles/PMC7917232/
  64. https://www.ahajournals.org/doi/10.1161/CIRCGEN.117.002210
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