Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: ADRB1
SNOMEDCT: 444981005;
Cytogenetic location: 10q25.3 Genomic coordinates (GRCh38): 10:114,043,866-114,046,904 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q25.3 | [Resting heart rate] | 607276 | 3 | |
| [Short sleep, familial natural, 2] | 618591 | Autosomal dominant | 3 |
The ADRB1 gene encodes the B1 adrenergic receptor, which is coupled to G proteins and stimulates the intracellular production of cAMP. A number of pharmacologically well-characterized subtypes of adrenergic receptors are known, including alpha-1 (ADRA1B; 104220), alpha-2 (e.g., ADRA2A; 104210), beta-1 (ADRB1), and beta-2 (ADRB2; 109690). Of these, both ADRB1 and ADRB2 stimulate adenylate cyclase, although they subserve different physiologic functions. A variety of drugs, both agonists and antagonists, selective for either beta-1 or beta-2 receptors have important applications in clinical medicine (summary by Frielle et al., 1987).
Frielle et al. (1987) reported the unexpected cloning of the human B1AR cDNA from a human placenta cDNA library screened with human genomic clone G-21. The G-21 clone, containing an intronless gene for an as yet unidentified putative receptor, was itself obtained by its cross-hybridization with the human gene encoding B2AR. The sequence of the cDNA encoding human B1AR was determined. The 2.4-kb cDNA for the human B1AR encodes a protein of 477 amino acid residues that is 69% homologous with the avian beta-adrenergic receptor but only 54% homologous with the human beta-2-adrenergic receptor. This suggested that the avian gene encoding BAR and the human gene encoding B1AR evolved from a common ancestral gene. Expression of the B1AR protein in Xenopus laevis oocytes conveyed adenylate cyclase responsiveness to catecholamines with a typical beta-1 specificity. This contrasts with the typical beta-2 subtype specificity observed when B2AR cDNAs expressed in the Xenopus laevis system. Thus, mammalian B1AR and B2AR are products of distinct genes, both of which are apparently related to the putative G-21 receptor. See review by Frielle et al. (1988).
Ellis and Frielle (1999) cloned full-length ADRB1 cDNAs of about 2.75 and 3.0 kb from a placenta cDNA library. The cDNAs differ only in the utilization of alternative polyadenylation sites. Both 3-prime UTRs are AU rich, and each contains several potential binding sites for mRNA stability factors. Northern blot analysis detected the 3.0-kb transcript in placenta. RNase protection analysis detected both transcripts in all tissues examined, including placenta, heart, cerebral cortex, and lung, as well as in a neuroblastoma cell line. The 3.0-kb transcript was expressed at 5 to 6 times the level of the 2.75-kb transcript. Expression of both transcripts decreased in failing hearts compared with nonfailing control hearts.
Xu et al. (2003) presented evidence that ADRA2A (104210) and ADRB1 form heterodimers when coexpressed in cultured cells, and that ADRA2A expression affects the internalization and ligand-binding characteristics of ADRB1.
Using nanoscale live-cell scanning ion conductance and fluorescence resonance energy transfer microscopy in cardiomyocytes from healthy adult rats and mice, Nikolaev et al. (2010) found that spatially confined beta-2 adrenergic receptor (ADRB2; 109690)-induced cAMP signals were localized exclusively to the deep transverse tubules, whereas functional beta-1 adrenergic receptors were distributed across the entire cell surface. In cardiomyocytes derived from a rat model of chronic heart failure, beta-2 adrenergic receptors were redistributed from the transverse tubules to the cell crest, which led to diffuse receptor-mediated cAMP signaling. Nikolaev et al. (2010) concluded that redistribution of beta-2 adrenergic receptors in heart failure changes compartmentation of cAMP and might contribute to the failing myocardial phenotype.
Magnusson et al. (1990) demonstrated autoantibodies against the beta-1-adrenergic receptor in some patients with idiopathic dilated cardiomyopathy (see 115200).
Crystal Structure
Warne et al. (2011) presented 4 crystal structures of the thermostabilized turkey beta-1-adrenergic receptor bound to the full agonists carmoterol and isoprenaline and the partial agonists salbutamol and dobutamine. In each case, agonist binding induced a 1-angstrom contraction of the catecholamine-binding pocket relative to the antagonist-bound receptor. Full agonists can form hydrogen bonds with 2 conserved serine residues in transmembrane helix 5 (ser5.42 and ser5.46), but partial agonists only interact with ser5.42.
Warne et al. (2019) determined 4 active-state crystal structures of the beta-1-adrenoceptor bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. Comparison with inactive-state structures of beta-1-adrenoceptor bound to the identical ligands showed a 24 to 42% reduction in the volume of the orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up to a 30% increase in the number of atomic contacts between the receptor and ligand. Warne et al. (2019) conclude their observations explain the increase in agonist affinity of G protein-coupled receptors in the active state for a wide range of structurally distinct agonists.
Lee et al. (2020) determined the cryoelectron microscopy structure of the ADRB1-beta-arrestin-1 (ARRB1; 107940) complex in lipid nanodiscs bound to the biased agonist formoterol, as well as the crystal structure of formoterol-bound ADRB1 coupled to the G-protein-mimetic nanobody Nb80. ARRB1 coupled to ADRB1 in a manner distinct from that of Gs coupling to ADRB2, as the finger loop of ARRB1 occupied a narrower cleft on the intracellular surface and was closer to transmembrane helix H7 of the receptor compared with the C-terminal alpha-5 helix of Gs. The finger loop adopted by ARRB1 was different from that of visual arrestin (ARR3; 301770) coupled to rhodopsin (RHO; 180380). ADRB1 coupled to ARRB1 showed considerable differences in structure compared with ADRB1 coupled to Nb80, including an inward movement of extracellular loop-3 and the cytoplasmic ends of H5 and H6. Lee et al. (2020) observed weakened interactions between formoterol and 2 serines in H5 at the orthosteric binding site of ADRB1 and found that formoterol had a lower affinity for the ADRB1-ARRB1 complex than for the ADRB1-Gs complex.
Mass Spectrometry
Using mass spectrometry to identify endogenous lipids bound to 3 G protein-coupled receptors of class A, Yen et al. (2018) observed preferential binding of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) over related lipids and confirmed that the intracellular surface of the receptors contain hotspots for PtdIns(4,5)P2 binding. Endogenous lipids were also observed bound directly to the trimeric G-alpha(s)-beta-gamma protein complex (see 139320) of the adenosine A2A receptor (ADORA2A; 102776) in the gas phase. Using engineered G-alpha subunits (mini-G-alpha(s), 139320; mini-G-alpha(i), see 139310; and mini-G-alpha(12), 604394), Yen et al. (2018) demonstrated that the complex of mini-G-alpha(s) with the beta-1 adrenergic receptor (ADRB1) is stabilized by the binding of 2 PtdIns(4,5)P2 molecules. By contrast, PtdIns(4,5)P2 does not stabilize coupling between ADRB1 and other G-alpha subunits (mini-G-alpha(i) or mini-G-alpha(12)) or a high-affinity nanobody. Other endogenous lipids that bind to these receptors had no effect on coupling, highlighting the specificity of PtdIns(4,5)P2.
By means of somatic cell hybrid analysis and in situ hybridization, Hoehe et al. (1989) localized the beta-1 adrenergic receptor gene to chromosome 10. Hoehe et al. (1989) concluded from linkage studies that the ADRB1R and ADRA2R loci are closely linked in the region 10q23-q25. Pulsed field gel electrophoresis showed that the 2 loci are in the same 250-kb segment. By in situ hybridization, Yang-Feng et al. (1990) regionalized the ADRA2R and ADRB1R genes to 10q24-q26. From studies by pulsed field gel electrophoresis, they concluded that the 2 genes are less than 225 kb apart. By linkage studies and interspecific backcrosses, Oakey et al. (1991) assigned the Adrb1r gene to the distal region of mouse chromosome 19.
Susceptibility to Congestive Heart Failure and Modification of Beta-Blocker Response
Mason et al. (1999) identified a nonsynonymous SNP (R389G; 109630.0001) in the ADRB1, which results in alterations of receptor-Gs interaction with functional consequences on signal transduction, consistent with its localization in a putative G-protein binding domain.
Sustained cardiac adrenergic stimulation has been implicated in the development and progression of heart failure. Release of norepinephrine is controlled by negative feedback from presynaptic alpha-2-adrenergic receptors, and the targets of the released norepinephrine on myocytes are beta-1-adrenergic receptors. In transfected cells, the R389G variant of the beta-1-adrenergic receptor has increased function, and a polymorphic alpha-2C-adrenergic receptor, del322-325 (104250.0001), has decreased function. Small et al. (2002) hypothesized that this combination of receptor variants, which results in increased synaptic norepinephrine release and enhanced receptor function at the myocyte, would predispose persons to heart failure. Genotyping at these loci was performed in 159 patients with heart failure and 189 controls. Among black subjects, the adjusted odds ratio for heart failure among persons who were homozygous for del322-325 as compared with those with the other ADRA2C phenotypes was 5.65. There was no increase in risk for ADRB1 arg389 alone. However, there was a marked increase in the risk of heart failure among persons who were homozygous for both variants (adjusted odds ratio, 10.11). The patients with heart failure did not differ from the controls in the frequencies of 9 short tandem repeat alleles. Among white subjects, there were too few who were homozygous for both polymorphisms to allow an adequate assessment of risk. Small et al. (2002) suggested that genotyping at these 2 loci may be a useful approach for identifying persons at risk for heart failure or its progression who may be candidates for early preventive measures.
Iwai et al. (2002) studied allele and genotype frequencies of the R389G polymorphism and clinical characteristics of 163 Japanese patients with dilated cardiomyopathy and 157 controls. They found that the gly389 allele was associated with a decreased risk of ventricular tachycardia (OR, 0.29 in patients carrying 1 or 2 copies of the gly389 allele; 95% CI, 0.13-0.64; p = 0.002).
In a cohort of 931 Caucasian women, Dionne et al. (2002) found that the arg389 allele of ADRB1 was associated with greater body weight and BMI, with each arg389 allele being associated with a 2.91 kg greater body weight (p = 0.01) and a 0.86 kg greater BMI (p = 0.05). In a subset of 214 women who underwent fuller characterization, the authors found that each arg389 allele was associated with greater fat mass (3.71 kg; p = 0.008).
In a study of 54 patients with congestive heart failure treated with the beta-blocker metoprolol, Lobmeyer et al. (2007) found that the ADRB1 R389G and the del322-325 ADRA2C polymorphisms synergistically influenced the ejection fraction response to beta-blocker therapy.
Variation in Resting Heart Rate
Ranade et al. (2002) investigated the genetic determination of resting heart rate (607276) which had been found in several studies to show significant correlation with cardiovascular morbidity and mortality. Because signaling through the beta-1-adrenergic receptor is a key determinant of cardiac function, they tested whether polymorphisms in this receptor are associated with resting heart rate. They studied a cohort of more than 1,000 individuals of Chinese and Japanese descent, from nuclear families, and genotyped 2 polymorphisms: ser49 to gly (S49G; 109630.0002) and R389G in the ADRB1 gene. For comparison, polymorphisms in the beta-2- and beta-3-adrenergic receptors (109690; 109691) were also evaluated. The S49G polymorphism was significantly associated (p = 0.0004) with resting heart rate, independent of other variables, such as body-mass index, age, sex, ethnicity, exercise, smoking, alcohol intake, hypertension status, and treatment with beta blockers. The data supported a tentative model in which individuals heterozygous for the S49G polymorphism had mean heart rates intermediate to those of either type of homozygote, with Ser homozygotes having the highest mean heart rate and with Gly homozygotes having the lowest. Neither the R389G polymorphism in the ADRB1 gene nor polymorphisms in the ADRB2 and ADRB3 genes were associated with resting heart rate. The heritability of heart rate was 39.7% +/- 7.1%.
Familial Natural Short Sleep 2
In affected members of a large multigenerational family (family 50025) with familial natural short sleep-2 (FNSS2; 618591), Shi et al. (2019) identified a heterozygous missense mutation in the ADRB1 gene (A187V; 109630.0003). The variant, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the phenotype in the family. It was found at a low frequency in the ExAC database (4.028 of 100,000 alleles). Mice with a heterozygous A187V mutation generated using CRISPR/Cas9 techniques demonstrated a short sleep phenotype, with increased mobile time during both the light and dark phases. Mice carrying the variant had about 55 minutes shorter total sleep time compared to wildtype mice, which affected both non-REM and REM sleep. Detailed studies in mice showed high expression of the ADRB1 gene in the dorsal pons within neurons that showed altered activity throughout the sleep cycle. ADRB1+ cells, which were primarily glutamatergic or GABAergic, were 'wake promoting.' Electrophysiologic properties and activity of the Adrb1+ neurons were altered by the A187V variant, with an overall increase in Adrb1+ neuron population activity and increased excitability. The variant showed a dominant effect. The findings suggested a role for ADRB1 receptors in regulation of the sleep/wake cycle.
Cagliani et al. (2009) analyzed the recent evolutionary history of the ADRB genes in humans, with particular concern to selective patterns. Their data suggested neutral selection for the ADRB1 gene, but deviations from neutrality for the ADRB2 and ADRB3 genes.
Rohrer et al. (1999) found that mice lacking both Adrb1 and Adrb2 had normal basal heart rate, blood pressure, and metabolic rate. However, stimulation with beta-receptor agonists or exercise revealed significant impairment in chronotropic range, vascular reactivity, and metabolic rate; maximal exercise capacity was not affected. Beta-receptor stimulation of cardiac inotropy and chronotropy was mediated almost exclusively by Adrb1, whereas vascular relaxation and metabolic rate were controlled by all 3 beta receptors. Compensatory alterations in cardiac muscarinic receptor density and vascular Adrb3 responsiveness were also observed in Adrb1/Adrb2 double-knockout mice.
To determine whether the sympathetic nervous system is the efferent arm of diet-induced thermogenesis, Bachman et al. (2002) created mice that lacked the beta-adrenergic receptors ADRB1, ADRB2, and ADRB3. Beta-less mice on a chow diet had a reduced metabolic rate and were slightly obese. On a high-fat diet, beta-less mice, in contrast to wildtype mice, developed massive obesity that was due entirely to a failure of diet-induced thermogenesis. Bachman et al. (2002) concluded that the beta-adrenergic receptors are necessary for diet-induced thermogenesis and that this efferent pathway plays a critical role in the body's defense against diet-induced obesity.
Mialet Perez et al. (2003) reported the targeted transgenic overexpression of beta-1 adrenergic receptor carrying the arg389 or the gly389 variant (109630.0001) in mouse ventricles, revealing an allele-specific cardiac phenotype that was recapitulated in human heart failure. Hearts from young arg389 mice had enhanced receptor function and contractility compared with gly389 hearts. Older arg389 mice displayed a phenotypic switch, with decreased beta-agonist signaling to adenylyl cyclase and decreased cardiac contractility compared with gly389 hearts. Arg389 hearts had abnormal expression of fetal and hypertrophy genes and calcium-cycling proteins, decreased adenylyl cyclase and G-alpha-s expression, and fibrosis with heart failure. This phenotype was recapitulated in homozygous, end-stage, failing human hearts. In addition, hemodynamic responses to beta-receptor blockade were greater in arg389 mice, and homozygosity for arg389 was associated with improvement in ventricular function during carvedilol treatment in heart failure patients. Mialet Perez et al. (2003) concluded that the human arg389 variant predisposes to heart failure by instigating hyperactive signaling programs leading to depressed receptor coupling and ventricular dysfunction, and influences the therapeutic response to beta-receptor blockade.
Jahns et al. (2004) gave monthly immunizations against the second extracellular beta-1-receptor loop to inbred rats, all of which developed receptor-stimulating anti-beta-1-receptor-loop antibodies and, after 9 months, progressive severe left ventricular dilatation and dysfunction. The authors transferred sera from antibody-positive and antibody-negative rats every month to healthy rats of the same strain. All rats that received the anti-beta-1-receptor-loop antibody also developed a similar cardiomyopathic phenotype within a similar time frame. Jahns et al. (2004) concluded that an autoimmune attack directed against the cardiac beta-1-adrenergic receptor may play a causal role in idiopathic dilated cardiomyopathy.
The beta-1-adrenergic receptor, a key cell surface signaling protein expressed in the heart and other organs, mediates the actions of catecholamines in the sympathetic nervous system. Mason et al. (1999) identified a C-to-G transversion in the intracellular cytoplasmic tail near the seventh transmembrane-spanning segment of the human ADRB1 gene, resulting in an arg389-to-gly substitution (R389G). Allele frequencies for gly389 and arg389 residues were 0.26 and 0.74, respectively (the former had previously been considered as the human wildtype ADRB1 allele). Using site-directed mutagenesis to mimic the 2 variants, cultured cells were permanently transfected to express the gly389 and arg389 receptors. In functional studies with matched expression, the arg389 receptors had slightly higher basal levels of adenylyl cyclase activities. However, maximal isoproterenol-stimulated levels were markedly higher for the arg389 receptor as compared with the gly389 receptor. Agonist-promoted binding was also increased for the arg389 receptor, consistent with enhanced coupling to stimulatory G protein (Gs; see 139320) and increased adenylyl cyclase activation. These and other studies indicated that this polymorphic variation of the human ADRB1 gene results in alterations of receptor-Gs interaction with functional consequences on signal transduction, consistent with its localization in a putative G-protein binding domain. Mason et al. (1999) suggested that the genetic variation of the ADRB1 gene may be the basis of interindividual differences in pathophysiologic characteristics or in the response to therapeutic beta-adrenergic receptor agonists and antagonists in cardiovascular and other diseases.
Among black subjects, Small et al. (2002) found an adjusted odds ratio for heart failure (10.11) in persons who were homozygous for both arg389 of the ADRB1 gene and for a 4-bp deletion (322-325del; 104250.0001) in the ADRA2C gene. Small et al. (2002) reasoned that the decreased function of the deletion polymorphism would reduce the control of norepinephrine by negative feedback from presynaptic alpha-2-adrenergic receptors, and that the increased function of the arg389 form of the beta-1-adrenergic receptor on myocytes would in combination result in increased synaptic norepinephrine release and enhanced receptor function at the myocyte, thus predisposing persons to heart failure. They found no increased risk with the arg389 allele alone.
Liggett et al. (2006) studied isolated right ventricular trabeculae from failing and nonfailing human hearts and observed that arg389 receptors had approximately 3- and 4-fold greater agonist-promoted contractility compared to gly389 receptors, respectively. The beta-blocker, bucindolol, was an inverse agonist in failing arg389, but not gly389, ventricles. In transfected cells, bucindolol antagonized agonist-stimulated cAMP, with a greater absolute decrease for arg389. In a placebo-controlled trial of bucindolol in 1,040 heart failure patients, no outcome was associated with genotype in the placebo group, indicating little impact on the natural course of heart failure. However, arg389 homozygotes treated with bucindolol had an age-, sex-, and race-adjusted 38% reduction in mortality (p = 0.03) and a 34% reduction in mortality or hospitalization (p = 0.004) versus placebo. Gly389 carriers had no clinical response to bucindolol compared with placebo. Liggett et al. (2006) concluded that the R389G variation alters signaling in multiple models and affects the therapeutic response to beta-blockers.
Lobmeyer et al. (2007) genotyped 54 patients with congestive heart failure for the R389G and del322-325 polymorphisms in the ADRB1 and ADRA2C genes, respectively, and performed echocardiography before and after treatment with the beta-blocker metoprolol. The authors found that patients homozygous for R389 who also carried del322-325 showed a significantly higher ejection fraction increase with metoprolol than all the other genotype combination groups, and concluded that the ADRB1 and ADRA2C polymorphisms synergistically influence the ejection fraction response to beta-blocker therapy of heart failure patients.
Ranade et al. (2002) found that heritability of heart rate was 39.7% +/- 7.1%. A significant association between resting heart rate (607276) and the ser49-to-gly polymorphism of the ADRB1 gene was found, independent of other variables. The data suggested that individuals heterozygous for the polymorphism had mean heart rates intermediate to those of either type of homozygote, with ser homozygotes having the highest mean heart rate and gly homozygotes having the lowest.
In affected members of a large multigenerational family (family 50025) with familial natural short sleep-2 (FNSS2; 618591), Shi et al. (2019) identified a heterozygous C-to-T transition in the ADRB1 gene, resulting in an ala187-to-val (A187V) substitution at a highly conserved residue in the fourth transmembrane domain. The variant, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the phenotype in the family. It was found at a low frequency in the ExAC database (4.028 of 100,000 alleles). In vitro functional expression studies in HEK293 cells showed that the variant protein was less stable and was associated with decreased cAMP production in response to stimulation compared to wildtype. Mice with a heterozygous A187V mutation generated using CRISPR/Cas9 techniques demonstrated a short sleep phenotype, with increased mobile time during both the light and dark phases. Mice carrying the variant had about 55 minutes shorter total sleep time compared to wildtype mice, which affected both non-REM and REM sleep. Detailed studies in mice showed high expression of the ADRB1 gene in the dorsal pons within neurons that showed altered activity throughout the sleep cycle. ADRB1+ cells, which were primarily glutamatergic or GABAergic, were 'wake promoting.' Electrophysiologic properties and activity of the Adrb1+ neurons were altered by the A187V variant, with an overall increase in Adrb1+ neuron population activity and increased excitability. The variant showed a dominant effect. The findings suggested a role for ADRB1 receptors in regulation of the sleep/wake cycle.
Bachman, E. S., Dhillon, H., Zhang, C.-Y., Cinti, S., Bianco, A. C., Kobilka, B. K., Lowell, B. B. Beta-AR signaling required for diet-induced thermogenesis and obesity resistance. Science 297: 843-845, 2002. [PubMed: 12161655] [Full Text: https://doi.org/10.1126/science.1073160]
Cagliani, R., Fumagalli, M., Pozzoli, U., Riva, S., Comi, G. P., Torri, F., Macciardi, F., Bresolin, N., Sironi, M. Diverse evolutionary histories for beta-adrenoreceptor genes in humans. Am. J. Hum. Genet. 85: 64-75, 2009. [PubMed: 19576569] [Full Text: https://doi.org/10.1016/j.ajhg.2009.06.005]
Dionne, I. J., Garant, M. J., Nolan, A. A., Pollin, T. I., Lewis, D. G., Shuldiner, A. R., Poehlman, E. T. Association between obesity and a polymorphism in the beta-1-adrenoceptor gene (gly389arg ADRB1) in Caucasian women. Int. J. Obes. Relat. Metab. Disord. 26: 633-639, 2002. [PubMed: 12032746] [Full Text: https://doi.org/10.1038/sj.ijo.0801971]
Ellis, C. E., Frielle, T. Characterization of two human beta-1-adrenergic receptor transcripts: cloning and alterations in the failing heart. Biochem. Biophys. Res. Commun. 258: 552-558, 1999. [PubMed: 10329424] [Full Text: https://doi.org/10.1006/bbrc.1999.0689]
Frielle, T., Collins, S., Daniel, K. W., Caron, M. G., Lefkowitz, R. J., Kobilka, B. K. Cloning of the cDNA for the human beta-1-adrenergic receptor. Proc. Nat. Acad. Sci. 84: 7920-7924, 1987. [PubMed: 2825170] [Full Text: https://doi.org/10.1073/pnas.84.22.7920]
Frielle, T., Kobilka, B., Lefkowitz, R. J., Caron, M. G. Human beta-1- and beta-2-adrenergic receptors: structurally and functionally related receptors derived from distinct genes. Trends Neurosci. 11: 321-324, 1988. [PubMed: 2465637] [Full Text: https://doi.org/10.1016/0166-2236(88)90095-1]
Hoehe, M., Berrettini, W., Leppert, M., Lalouel, J.-M., Byerley, W., Gershon, E., White, R. Genetic mapping of adrenergic receptor genes. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A143 only, 1989.
Iwai, C., Akita, H., Shiga, N., Takai, E., Miyamoto, Y., Shimizu, M., Kawai, H., Takarada, A., Kajiya, T., Yokoyama, M. Suppressive effect of the gly389 allele of the 1-adrenergic receptor gene on the occurrence of ventricular tachycardia in dilated cardiomyopathy. Circ. J. 66: 723-728, 2002. [PubMed: 12197595] [Full Text: https://doi.org/10.1253/circj.66.723]
Jahns, R., Boivin, V., Hein, L., Triebel, S., Angermann, C. E., Ertl, G., Lohse, M. J. Direct evidence for a beta-1-adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy. J. Clin. Invest. 113: 1419-1429, 2004. [PubMed: 15146239] [Full Text: https://doi.org/10.1172/JCI20149]
Kannel, W. B., Kannel, C., Paffenbarger, R. S., Jr., Cupples, L. A. Heart rate and cardiovascular mortality: the Framingham Study. Am. Heart J. 113: 1489-1494, 1987. [PubMed: 3591616] [Full Text: https://doi.org/10.1016/0002-8703(87)90666-1]
Lee, Y., Warne, T., Nehme, R., Pandey, S., Dwivedi-Angihotri, H., Chaturvedi, M., Edwards, P. C., Garcia-Nafria, J., Leslie, A. G. W., Shukla, A. K., Tate, C. G. Molecular basis of beta-arrestin coupling to formoterol-bound beta-1-adrenoceptor. Nature 583: 862-866, 2020. [PubMed: 32555462] [Full Text: https://doi.org/10.1038/s41586-020-2419-1]
Liggett, S. B., Mialet-Perez, J., Thaneemit-Chen, S., Weber, S. A., Greene, S. M., Hodne, D., Nelson, B., Morrison, J., Domanski, M. J., Wagoner, L. E., Abraham, W. T., Anderson, J. L., Carlquist, J. F., Krause-Steinrauf, H. J., Lazzeroni, L. C., Port, J. D., Lavori, P. W., Bristow, M. R. A polymorphism within a conserved beta-1-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc. Nat. Acad. Sci. 103: 11288-11293, 2006. [PubMed: 16844790] [Full Text: https://doi.org/10.1073/pnas.0509937103]
Lobmeyer, M. T., Gong, Y., Terra, S. G., Beitelshees, A. L., Langaee, T. Y., Pauly, D. F., Schofield, R. S., Hamilton, K. K., Patterson, J. H., Adams, K. F., Jr., Hill, J. A., Aranda, J. M., Jr., Johnson, J. A. Synergistic polymorphisms of beta-1 and alpha-2C-adrenergic receptors and the influence on left ventricular ejection fraction response to beta-blocker therapy in heart failure. Pharmacogenet. Genomics 17: 277-282, 2007. [PubMed: 17496726] [Full Text: https://doi.org/10.1097/FPC.0b013e3280105245]
Magnusson, Y., Marullo, S., Hoyer, S., Waagstein, F., Andersson, B., Vahlne, A., Guillet, J.-G., Strosberg, A. D., Hjalmarson, A., Hoebeke, J. Mapping of a functional autoimmune epitope on the beta(1)-adrenergic receptor in patients with idiopathic dilated cardiomyopathy. J. Clin. Invest. 86: 1658-1663, 1990. [PubMed: 1700798] [Full Text: https://doi.org/10.1172/JCI114888]
Mason, D. A., Moore, J. D., Green, S. A., Liggett, S. B. A gain-of-function polymorphism in a G-protein coupling domain of the human beta-1-adrenergic receptor. J. Biol. Chem. 274: 12670-12674, 1999. [PubMed: 10212248] [Full Text: https://doi.org/10.1074/jbc.274.18.12670]
Mialet Perez, J., Rathz, D. A., Petrashevskaya, N. N., Hahn, H. S., Wagoner, L. E., Schwartz, A., Dorn, G. W., II, Liggett, S. B. Beta-1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nature Med. 9: 1300-1305, 2003. [PubMed: 14502278] [Full Text: https://doi.org/10.1038/nm930]
Nikolaev, V. O., Moshkov, A., Lyon, A. R., Miragili, M., Novak, P., Paur, H., Lohse, M. J., Korchev, Y. E., Harding, S. E., Gorelik, J. Beta-2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science 327: 1653-1657, 2010. [PubMed: 20185685] [Full Text: https://doi.org/10.1126/science.1185988]
Oakey, R. J., Caron, M. G., Lefkowitz, R. J., Seldin, M. F. Genomic organization of adrenergic and serotonin receptors in the mouse: linkage mapping of sequence-related genes provides a method for examining mammalian chromosome evolution. Genomics 10: 338-344, 1991. [PubMed: 1676978] [Full Text: https://doi.org/10.1016/0888-7543(91)90317-8]
Ranade, K., Jorgenson, E., Sheu, W. H.-H., Pei, D., Hsiung, C. A., Chiang, F., Chen, Y. I., Pratt, R., Olshen, R. A., Curb, D., Cox, D. R., Botstein, D., Risch, N. A polymorphism in the beta-1 adrenergic receptor is associated with resting heart rate. Am. J. Hum. Genet. 70: 935-942, 2002. [PubMed: 11854867] [Full Text: https://doi.org/10.1086/339621]
Rohrer, D. K., Chruscinski, A., Schauble, E. H., Bernstein, D., Kobilka, B. K. Cardiovascular and metabolic alterations in mice lacking both beta-1- and beta-2-adrenergic receptors. J. Biol. Chem. 274: 16701-16708, 1999. [PubMed: 10358009] [Full Text: https://doi.org/10.1074/jbc.274.24.16701]
Shi, G., Xing, L., Wu, D., Bhattacharyya, B. J., Jones, C. R., McMahon, T., Chong, S. Y. C., Chen, J. A., Coppola, G., Geschwind, D., Krystal, A., Ptacek, L. J., Fu, Y.-H. A rare mutation of beta-1-adrenergic receptor affects sleep/wake behaviors. Neuron 103: 1044-1055, 2019. [PubMed: 31473062] [Full Text: https://doi.org/10.1016/j.neuron.2019.07.026]
Small, K. M., Wagoner, L. E., Levin, A. M., Kardia, S. L. R., Liggett, S. B. Synergistic polymorphisms of beta-1- and alpha-2C-adrenergic receptors and the risk of congestive heart failure. New Eng. J. Med. 347: 1135-1142, 2002. [PubMed: 12374873] [Full Text: https://doi.org/10.1056/NEJMoa020803]
Warne, T., Edwards, P. C., Dore, A. S., Leslie, A. G. W., Tate, C. G. Molecular basis for high-affinity agonist binding in GPCRs. Science 364: 775-778, 2019. [PubMed: 31072904] [Full Text: https://doi.org/10.1126/science.aau5595]
Warne, T., Moukhametzianov, R., Baker, J. G., Nehme, R., Edwards, P. C., Leslie, A. G. W., Schertler, G. F. X., Tate, C. G. The structural basis for agonist and partial agonist action on a beta-1-adrenergic receptor. Nature 469: 241-244, 2011. [PubMed: 21228877] [Full Text: https://doi.org/10.1038/nature09746]
Xu, J., He, J., Castleberry, A. M., Balasubramanian, S., Lau, A. G., Hall, R. A. Heterodimerization of alpha-2A- and beta-1-adrenergic receptors. J. Biol. Chem. 278: 10770-10777, 2003. [PubMed: 12529373] [Full Text: https://doi.org/10.1074/jbc.M207968200]
Yang-Feng, T. L., Xue, F., Zhong, W., Cotecchia, S., Frielle, T., Caron, M. G., Lefkowitz, R. J., Francke, U. Chromosomal organization of adrenergic receptor genes. Proc. Nat. Acad. Sci. 87: 1516-1520, 1990. [PubMed: 2154750] [Full Text: https://doi.org/10.1073/pnas.87.4.1516]
Yen, H.-Y., Hoi, K. K., Liko, I., Hedger, G., Horrell, M. R., Song, W., Wu, D., Heine, P., Warne, T., Lee, Y., Carpenter, B., Pluckthun, A., Tate, C. G., Sansom, M. S. P., Robinson, C. V. PtdIns(4,5)P2 stabilizes active states of GPCRs and enhances selectivity of G-protein coupling. Nature 559: 423-427, 2018. [PubMed: 29995853] [Full Text: https://doi.org/10.1038/s41586-018-0325-6]