Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: ADRB2
Cytogenetic location: 5q32 Genomic coordinates (GRCh38): 5:148,826,611-148,828,623 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q32 | Beta-2-adrenoreceptor agonist, reduced response to | 3 |
Kobilka et al. (1987) reported the cloning and complete nucleotide sequence of the cDNA for human beta-2-adrenergic receptor. The deduced amino acid sequence (413 residues) encodes a protein containing 7 clusters of hydrophobic amino acids suggestive of membrane-spanning domains. While the protein shows 87% identity overall with the previously cloned hamster beta-2-adrenergic receptor, the most highly conserved regions are the putative transmembrane helices (95% identical) and cytoplasmic loops (93% identical), suggesting that these regions of the molecule harbor important functional domains.
Whereas the rhodopsin gene (180380) consists of 5 exons interrupted by 4 introns, the beta-adrenergic receptor genes contain no introns in either their coding or untranslated sequences (Kobilka et al., 1987).
Emorine et al. (1987) characterized the promoter region of the gene.
Because of a lack of beta-adrenergic receptors, Chinese hamster fibroblasts do not respond to the beta-adrenergic agonist with an increase in cellular cAMP. Thus, by study of hamster-human somatic cell hybrids, Sheppard et al. (1983) could assign to human chromosome 5 the structural gene for the beta-2-adrenergic receptor.
By studies in somatic cell hybrids and by in situ hybridization, Kobilka et al. (1987) localized the gene to 5q31-q32. This position is the same as that for the gene coding for platelet-derived growth factor receptor (173410) and is adjacent to the site of the FMS oncogene (164770), the receptor for CSF1 (120420). By in situ hybridization, Yang-Feng et al. (1990) regionalized the assignment to 5q32-q34. By analysis of interspecific backcrosses, Oakey et al. (1991) mapped the corresponding mouse gene, symbolized Adrb2, to the proximal portion of chromosome 18.
Crystal Structure
Cherezov et al. (2007) reported the crystal structure of a human beta-2 adrenergic receptor-T4 lysozyme fusion protein bound to the partial inverse agonist carazolol at 2.4-angstrom resolution. The structure provides a high-resolution view of a human G protein-coupled receptor bound to a diffusible ligand. Ligand-binding site accessibility is enabled by the second extracellular loop, which is held out of the binding cavity by a pair of closely spaced disulfide bridges and a short helical segment within the loop. Cholesterol, a necessary component for crystallization, mediates an intriguing parallel association of receptor molecules in the crystal lattice. Although the location of carazolol in the beta-2-adrenergic receptor is very similar to that of retinal in rhodopsin (180380), structural differences in the ligand-binding site and other regions highlight the challenges in using rhodopsin as a template model for this large receptor family.
Rosenbaum et al. (2007) reported that to overcome the structural flexibility of the beta-2-adrenergic receptor and to facilitate its crystallization, they engineered a beta-2-adrenergic receptor fusion protein in which T4 lysozyme replaces most of the third intracellular loop of the G protein-coupled receptor and showed that this protein retains near-native pharmacologic properties. Analysis of adrenergic receptor ligand-binding mutants within the context of the reported high-resolution structure of the fusion protein provided insights into inverse-agonist binding and the structural changes required to accommodate catecholamine agonists. Amino acids known to regulate receptor function are linked through packing interactions and a network of hydrogen bonds, suggesting a conformational pathway from the ligand-binding pocket to regions that interact with G proteins.
Rasmussen et al. (2007) reported a structure of the human beta-2 adrenoceptor (beta-2-AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4-angstrom/3.7-angstrom resolution. The cytoplasmic ends of the beta-2-AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta-2-AR are not seen. The beta-2-AR structure differs from rhodopsin in having weaker interactions between the cytoplasmic ends of transmembrane domains 3 and 6, involving the conserved E/DRY sequences. Rasmussen et al. (2007) concluded that these differences may be responsible for the relatively high basal activity and structural instability of the beta-2-AR, and contribute to the challenges of obtaining diffraction-quality crystals of non-rhodopsin G protein-coupled receptors.
Rasmussen et al. (2011) generated a camelid antibody fragment, which they called a nanobody, to the beta-2-AR that exhibits G protein-like behavior, and obtained an agonist-bound, active-state crystal structure of the receptor-nanobody complex. Comparison with the inactive beta-2-AR structure revealed subtle changes in the binding pocket; however, these small changes were associated with an 11-angstrom outward movement of the cytoplasmic end of transmembrane segment 6, and rearrangements of transmembrane segments 5 and 7 that were remarkably similar to those observed in opsin, an active form of rhodopsin.
Rosenbaum et al. (2011) used the inactive structure of the human beta-2-AR as a guide to design a beta-2-AR agonist that can be covalently tethered to a specific site on the receptor through a disulfide bond. The covalent beta-2-AR-agonist complex formed efficiently, and was capable of activating a heterotrimeric G protein. Rosenbaum et al. (2011) crystallized a covalent agonist-bound beta-2-AR-T4L fusion protein in lipid bilayers through the use of lipidic mesophase method, and determined its structure at 3.5-angstrom resolution. A comparison to the inactive structure and an antibody-stabilized active structure showed how binding events at both the extracellular and intracellular surfaces are required to stabilize an active conformation of the receptor. The structures were in agreement with long-timescale (up to 30 microseconds) molecular dynamics stimulations showing that an agonist-bound active conformation spontaneously relaxes to an inactive-like conformation in the absence of a G protein or stabilizing antibody.
Rasmussen et al. (2011) presented the crystal structure of the active state ternary complex composed of agonist-occupied monomeric beta-2-AR and nucleotide-free Gs (139320) heterotrimer. The principal interactions between the beta-2-AR and Gs involve the amino- and carboxy-terminal alpha-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the beta-2-AR include a 14-angstrom outward movement at the cytoplasmic end of transmembrane segment 6 and an alpha-helical extension of the cytoplasmic end of transmembrane segment 5. The most surprising observation is a major displacement of the alpha-helical domain of G-alpha-s relative to the Ras-like GTPase domain.
Chung et al. (2011) applied peptide amide hydrogen-deuterium exchange mass spectrometry to probe changes in the structure of the heterotrimeric bovine G protein, Gs, on formation of a complex with agonist-bound human beta-2-AR. They reported structural links between the receptor-binding surface and the nucleotide-binding pocket of Gs that undergo higher levels of hydrogen-deuterium exchange than would be predicted from the crystal structure of the beta-2-AR-Gs complex. Together with x-ray crystallographic and electron microscopic data of the beta-2-AR-Gs complex, Chung et al. (2011) provided a rationale for a mechanism of nucleotide exchange, whereby the receptor perturbs the structure of the amino-terminal region of the alpha-subunit of Gs and consequently alters the 'P-loop' that binds the beta-phosphate in GDP.
Using oligonucleotide directed site-specific mutagenesis, Fraser et al. (1988) accomplished point mutation at nucleotide 388 of the BAR gene. The mutation resulted in a guanine-to-adenine substitution, exchanging an asparagine for a highly conserved aspartic acid at residue 130 of the human beta-adrenergic receptor. The mutant beta-adrenergic receptor appeared capable of interacting with the stimulatory guanine nucleotide-binding regulatory protein, but the ability of guanine nucleotides to alter agonist affinity was attenuated.
Luttrell et al. (1999) demonstrated that activated beta-2-adrenergic receptor binds beta-arrestin-1 (ARRB1; 107940), which then binds c-src (190090) at its amino terminus. This interaction targets the complex to clathrin-coated pits and allows for beta-2-adrenergic activation of the MAP kinases ERK1 (601795) and ERK2 (176948).
Patients with nocturnal asthma represent a subset of asthmatics who experience a marked worsening of airway obstruction and symptoms while asleep. Nocturnal asthmatics display greater bronchial hyperreactivity than do nonnocturnal asthmatics. Several studies had suggested that autonomic function may be different in nocturnal asthma as compared to nonnocturnal asthma. Szefler et al. (1991) found that circulating neutrophil and lymphocyte beta-2-adrenergic receptors, which are potential markers for ADRB2s of bronchial smooth muscle and other lung cells, decrease at 4:00 a.m. as compared to 4:00 p.m. in patients with nocturnal asthma. No such downregulation of ADRB2 was found in nonnocturnal asthmatics or normal subjects.
Davare et al. (2001) found that the beta-2 adrenergic receptor is directly associated with one of its ultimate effectors, the class C L-type calcium channel Ca(V)1.2 (114206). This complex also contains a G protein, an adenylyl cyclase (see 103070), cAMP-dependent kinase (see 601639), and the counterbalancing phosphatase PP2A (see 605997). Davare et al. (2001) used electrophysiologic recordings from hippocampal neurons to demonstrate highly localized signal transduction from the receptor to the channel. The assembly of this signaling complex provides a mechanism that ensures specific and rapid signaling by a G protein-coupled receptor.
Although trafficking and degradation of several membrane proteins are regulated by ubiquitination catalyzed by E3 ubiquitin ligases, the connection of ubiquitination with regulation of mammalian G protein-coupled receptor function has been unclear. Shenoy et al. (2001) demonstrated that agonist stimulation of endogenous or transfected beta-2 adrenergic receptors led to rapid ubiquitination of both the receptors and the receptor regulatory protein, beta-arrestin (ARRB2; 107941). Moreover, proteasome inhibitors reduced receptor internalization and degradation, thus implicating a role for the ubiquitination machinery in the trafficking of the beta-2 adrenergic receptor. Receptor ubiquitination required beta-arrestin, which bound the E3 ubiquitin ligase MDM2 (164785). Abrogation of beta-arrestin ubiquitination, either by expression in MDM2-null cells or by dominant-negative forms of MDM2 lacking E3 ligase activity, inhibited receptor internalization with marginal effects on receptor degradation. However, an ADRB2 mutant lacking lysine residues, which was not ubiquitinated, was internalized normally but was degraded ineffectively. Shenoy et al. (2001) concluded that their results delineated an adaptor role of beta-arrestin in mediating the ubiquitination of the beta-2 adrenergic receptor and indicated that ubiquitination of the receptor and of beta-arrestin have distinct and obligatory roles in the trafficking and degradation of this prototypic G protein-coupled receptor.
Harrison et al. (2003) demonstrated that signaling via the erythrocyte beta-2 adrenergic receptor and heterotrimeric guanine nucleotide-binding protein (GNAS; 139320) regulated the entry of the human malaria parasite Plasmodium falciparum. Agonists that stimulate cAMP production led to an increase in malarial infection that could be blocked by specific receptor antagonists. Moreover, peptides designed to inhibit GNAS protein function reduced parasitemia in P. falciparum cultures in vitro, and beta-antagonists reduced parasitemia of P. berghei infections in an in vivo mouse model. Harrison et al. (2003) suggested that signaling via the erythrocyte beta-2-adrenergic receptor and GNAS may regulate malarial infection across parasite species.
By analyzing Adrb2-deficient mice, Elefteriou et al. (2005) demonstrated that the sympathetic nervous system favors bone resorption by increasing expression in osteoblast progenitor cells of the osteoclast differentiation factor Rankl (602642). This sympathetic function requires phosphorylation by protein kinase A (PKA; see 176911) of ATF4 (604064), a cell-specific CREB (123810)-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biologic importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART (602606), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Elefteriou et al. (2005) concluded that their study established that leptin-regulated neural pathways control both aspects of bone remodeling, and demonstrated that integrity of sympathetic signaling is necessary for the increase in bone resorption caused by gonadal failure.
In HEK293 cells in vitro, Ni et al. (2006) found that activation of ADRB2 receptors stimulated gamma-secretase activity and beta-amyloid (APP; 104760) production. Stimulation involved the association of ADRB2 with PSEN1 (104311) and required agonist-induced endocytosis of ADRB2. Similar effects were observed after activation of the opioid receptor OPRD1 (165195). In mouse models of Alzheimer disease (AD; 104300), chronic treatment with ADRB2 agonists increased cerebral amyloid plaques, and treatment with ADRB2 antagonists reduced cerebral amyloid plaques. Ni et al. (2006) postulated that abnormal activation of ADRB2 receptors may contribute to beta-amyloid accumulation in AD.
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-induced cAMP signals were localized exclusively to the deep transverse tubules, whereas functional beta-1 adrenergic receptors (ADRB1; 109630) were distributed across the entire cell surface.
Using immunofluorescence microscopy, Coureuil et al. (2010) demonstrated that Neisseria meningitidis (Nm) colonies at the cell surface of human brain endothelial cells promoted translocation of ARRB1 and ARRB2 to the inner surface of the plasma membrane, facing the bacteria. ARRBs translocated under the colonies served as a scaffolding platform for signaling events elicited by Nm. ADRB2 was the only G protein-coupled receptor expressed in the cell line that played a permissive role in the formation of cortical plaques under colonies and in bacterial crossing of cell monolayers. Coureuil et al. (2010) concluded that the ADRB2/ARRB signaling pathway is required for Nm to promote stable adhesion to brain endothelial cells and subsequent crossing of the blood-brain barrier.
Using an unbiased screen targeting endogenous gene expression, Mittal et al. (2017) discovered that the beta-2-adrenoreceptor (B2AR) is a regulator of the alpha-synuclein gene (SNCA; 163890). B2AR ligands modulate SNCA transcription through histone H3 lysine-27 acetylation (H3K27ac) of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians, the B2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing Parkinson disease (PD; see 168600) (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76). Conversely, a B2AR antagonist, propanolol, correlated with increased risk. B2AR activation protected model mice and patient-derived cells. Thus, Mittal et al. (2017) concluded that B2AR is linked to transcription of alpha-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.
Reihsaus et al. (1993) found 6 different polymorphic forms of ADRB2. These polymorphisms consisted of amino acid substitutions. When they were mimicked by site-directed mutagenesis of the cloned human ADRB2 cDNA and expressed in Chinese hamster fibroblasts, some were found to display different pharmacologic properties. Specifically, they found that glycine at position 16 (R16G; 109690.0001), rather than arginine, imparted enhanced agonist-promoted downregulation. This prompted them to determine ADRB2 phenotypes of 2 well-defined asthmatic cohorts: 23 nocturnal asthmatics with 34% nocturnal depression of peak expiratory flow rates and 22 nonnocturnal asthmatics with virtually no such depression (2.3%). The frequency of the gly16 allele was 80.4% in the nocturnal group as compared to 52.2% in the nonnocturnal group, while the arg16 allele was present in 19.6% of the nocturnal group and 47.8% of the nonnocturnal group. Turki et al. (1995) hypothesized that gly16 may be overrepresented in nocturnal asthma. This overrepresentation of the gly16 allele in nocturnal asthma was significant at p = 0.007, with a 3.8 odds ratio for having both nocturnal asthma and the gly16 polymorphism. Comparisons of the 2 cohorts as to homozygosity for gly16, homozygosity for arg16, or heterozygosity were also consistent with segregation of gly16 with nocturnal asthma. There was no difference in the frequency of the gln27-to-glu (Q27E; 109690.0002) and thr164-to-ile (T164I; 109690.0003) polymorphisms between the 2 groups.
In a metaanalysis of 28 published studies, Contopoulos-Ioannidis et al. (2005) found an association between the gly16 polymorphism and nocturnal asthma, but found no association between the R16G or Q27E variants and asthma susceptibility overall or bronchial hyperresponsiveness.
The beta-2-adrenergic receptor agonists are the most widely used agents in the treatment of asthma, but the genetic determinants of responsiveness to these agents are unknown. It had been reported that gly16 (see 109690.0001) is associated with increased agonist-promoted downregulation of ADRB2 as compared with arg16. A form of the receptor with glu27 had been shown to be resistant to downregulation when compared with gln27 (109690.0002), but only when coexpressed with arg16. In a group of 269 children in a longitudinal study of asthma, Martinez et al. (1997) performed spirometry before and after administration of albuterol and correlated the findings with the genotypes of these 2 polymorphisms. Two polymorphisms showed marked linkage disequilibrium, with 97.8% of all chromosomes that carried arg16 also carrying gln27. When compared to homozygotes for gly16, homozygotes for arg16 were 5.3 times and heterozygotes for gly16 were 2.3 times more likely to respond to albuterol, respectively. Similar trends were observed for asthmatic and nonasthmatic children, and results were independent of baseline lung function, ethnic origin, and previous use of antiasthma medication. No association was found between glu27 and response to albuterol.
In a study of 190 asthmatics, Israel et al. (2001) found that the homozygous arg16 genotype of the ADRB2 gene was positively associated with an acute response to treatment, but was also associated with a significant decrease in response after regular use of beta-agonists, whereas the gly-gly genotype showed no change with regular use.
In a discussion of genetic polymorphism of drug targets, one aspect of pharmacogenomics, Evans and McLeod (2003) discussed genetic polymorphisms of the ADRB2 gene that alter the process of signal transduction by the beta-2-adrenergic receptor. They stated that the R16G (109690.0001) and Q27E (109690.0002) substitutions are relatively common, with allele frequencies of 0.4 to 0.6. They noted that Drysdale et al. (2000) had identified 13 distinct SNPs in ADRB2, which were organized into 12 haplotypes and that this finding led to evaluation of the importance of haplotype structure as compared with individual SNPs in determining receptor function and pharmacologic response.
Associations Pending Confirmation
In a study of 65 healthy and drug-free subjects, Lonnqvist et al. (1992) demonstrated that some individuals have resistance to the lipolytic effects of catecholamines and that this is the result of decreased ADRB2 expression in fat cells. The resistance was studied in vivo and in isolated abdominal subcutaneous adipocytes. Some of the plotted data demonstrated bimodality consistent with a relatively simple genetic basis for the difference. Whether the genetic difference is located at the ADRB2 locus or at another site was unclear. The clinical consequence of catecholamine resistance in apparently healthy subjects was also not clear.
It is well established that obesity is under strong genetic influence, with up to 40% of the variation in body fat content being attributed to genetic factors. Genes that are involved in the regulation of catecholamine function may be of particular importance for human obesity because of the central role catecholamines play in energy expenditure, both as hormones and as neurotransmitters. This regulation is in part affected by stimulating lipid mobilization through lipolysis in fat cells. The beta-2 adrenoceptor is a major lipolytic receptor in human fat cells. Large et al. (1997) investigated whether the common polymorphisms arg16 to gly and gln27 to glu are related to obesity. They found that gln27 to glu was indeed markedly associated with obesity with a relative risk for obesity of approximately 7 and an odds ratio of approximately 10. Homozygotes for glu27 had an average fat mass excess of 20 kg and approximately 50% larger fat cells than controls. However, no significant association with changes in ADRB2 function was observed. The polymorphism arg16gly was associated with altered ADRB2 function, with gly16 carriers showing a 5-fold increased agonist sensitivity without any change in ADRB2 expression. However, it was not significantly linked with obesity. The findings of Large et al. (1997) suggested that genetic variation in the ADRB2 gene may be of major importance for obesity, energy expenditure, and lipolytic ADRB2 function in adipose tissue, at least in women.
By PCR-direct sequencing, Yamada et al. (1999) screened the 5-prime untranslated region of the ADRB2 gene from 40 obese subjects. They identified 2 polymorphic sites: a T-to-C transition at -47 and a T-to-C transition at -20. By PCR and restriction digestion, they further analyzed the association of these polymorphisms with obesity in 574 subjects. The -47T-C substitution was in tight linkage disequilibrium with the -20T-C substitution. These polymorphisms were also in linkage disequilibrium with codon 16 and codon 27 polymorphisms. Subjects carrying the -47C/-20C allele had greater body mass index (25.5 +/- 4.5 vs 24.4 +/- 4.1 kg/m2; p = 0.007) and higher serum triglyceride levels (166 +/- 160 vs 139 +/- 95 mg/dl; p = 0.015) than -47T/-20T homozygotes. The variant allele frequency was significantly higher in obese subjects than in nonobese subjects (0.18 vs 0.11; p = 0.0026). Furthermore, an increased frequency of the variant allele was shown in diabetic patients compared with nondiabetic subjects (0.19 vs 0.11; p = 0.0005). The authors pointed out that the association may be attributable to the greater proportion of diabetic patients in the obese group. They suggested that the exchange at -47 may alter the expression level of the ADRB2 gene, because the nucleotide substitution at -47 results in a cys-to-arg exchange at the C terminal of the leader peptide.
The distal end of 5q, 5q31.1-qter, contains the genes for 2 adrenergic receptors, ADRB2 and ADRA1B (104220), and the dopamine receptor type 1A gene (DRD1A; 126449). Krushkal et al. (1998) used an efficient discordant sib-pair ascertainment scheme to investigate the impact of this region of the genome on variation in systolic blood pressure in young Caucasians. They measured 8 highly polymorphic markers spanning this positional candidate gene-rich region in 427 individuals from 55 3-generation pedigrees containing 69 discordant sib pairs, and calculated multipoint identity by descent probabilities. The results of genetic linkage and association tests indicated that the region between markers D5S2093 and D5S462 was significantly linked to one or more polymorphic genes influencing interindividual variation in systolic blood pressure levels. Since the ADRA1B and DRD1A genes are located close to these markers, the data suggested that genetic variation in one or both of these G protein-coupled receptors, which participate in the control of vascular tone, play an important role in influencing interindividual variation in systolic blood pressure levels.
Dallongeville et al. (2003) studied the association between the G16R (109690.0001) and Q27E (109690.0002) polymorphisms of the ADRB2 receptor and metabolic syndrome (605552) in 276 male and female patients with metabolic syndrome and 872 controls. Metabolic syndrome was defined according to National Cholesterol Education Program Adult Treatment Panel III guidelines. The G16R (P less than 0.005) and Q27E (P less than 0.04) polymorphisms were associated with metabolic syndrome in men, but not in women. Because both variants were in linkage disequilibrium, a haplotype analysis was performed. There was no evidence of any statistically significant association between ADRB2 haplotypes and metabolic syndrome.
Cagliani et al. (2009) analyzed the recent evolutionary history of the ADRB genes in humans, with particular concern to selective patterns. Although their data suggested neutral selection for the ADRB1 gene, most tests rejected neutral evolution for the ADRB2 and ADRB3 genes. Selection of specific ADRB2 alleles was found particularly in European, African, and Asian samples. The inferred ADRB2 haplotypes partitioned into 3 major clades with a coalescence time of 1 to 1.5 million years, suggesting that the ADRB2 gene is either subject to balanced selection or undergoing a selective sweep. Haplotype analysis also revealed ethnicity-specific differences. There was significant deviations from Hardy-Weinberg equilibrium (HWE) for ADRB2 genotypes in distinct European cohorts; HWE deviation depended on sex (females were in disequilibrium), and genotypes displaying maximum and minimum relative fitness differed across population samples, suggesting a complex situation possibly involving epistasis or maternal selection.
Wilson et al. (2010) noted errors in the chimpanzee Adrb sequence used by Cagliani et al. (2009) to estimate the node for appearance of the human most recent common ancestor (MRCA). The correction suggested a significantly more ancient MRCA for this gene. Wilson et al. (2010) also reviewed haplotypes at the 3-prime end of the ADRB2 gene that were not addressed by Cagliani et al. (2009). In a response from the Cagliani group, Fumagalli et al. (2010) noted the data correction and recalculated the time to MRCA as 1.9 million years. They proposed that this increased depth provides further support that ADRB2 has been evolving under a balancing-selection regime.
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.
Maurice et al. (1999) tested the hypothesis that genetic manipulation of the myocardial beta-adrenergic receptor system, which is impaired in heart failure, can enhance cardiac function. They delivered adenoviral transgenes, including human B2AR, to the myocardium of rabbits using an intracoronary approach. Catheter-mediated delivery of Adeno-B2AR produced diffuse multichamber myocardial expression, peaking 1 week after gene transfer. The delivery of the transgene reproducibly produced 5- to 10-fold B2AR overexpression in the heart, which, at 7 and 21 days after delivery, resulted in increased in vivo hemodynamic function, compared with control rabbits that received an empty adenovirus.
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.
Odley et al. (2004) developed transgenic mice expressing constitutively active (GTPase-deficient) or dominant-inhibitory (non-GTP-binding) Rab4 (179511) mutants. Expression of constitutively active Rab4 had no effect on cardiac structure or function, but the dominant-inhibitory Rab4 mutant impaired the responsiveness of Adrb2 to endogenous and exogenous catecholamines. These defects were accompanied by bizarre vesicular structures and abnormal accumulation of Adrb2 in the sarcoplasm and subsarcolemma. Odley et al. (2004) presented further evidence that Rab4 is involved in bidirectional sarcolemmal-vesicular Adrb2 trafficking, which occurs continuously in healthy hearts and is necessary for normal baseline adrenergic responsiveness and resensitization after catecholamine exposure.
This variant, formerly titled ASTHMA, NOCTURNAL, SUSCEPTIBILITY TO, has been reclassified as a polymorphism based on its frequency in the gnomAD database. Hamosh (2023) noted that the variant was present in 119,058 of 282,464 alleles and in 25,781 homozygotes in gnomAD (v2.1.1).
Turki et al. (1995) found an excess of gly16, as opposed to arg16, among individuals with nocturnal asthma (see 600807). Other evidence has suggested that the presence of glycine at position 16 of B2AR imparts enhanced agonist-promoted downregulation of the type that characterizes this form of asthma. See also Martinez et al. (1997).
Hopes et al. (1998) found no relation between gly16 and childhood asthma.
In a randomized, placebo-controlled, crossover study involving 78 patients with mild asthma, 37 with the R/R genotype and 41 with the G/G genotype, Israel et al. (2004) found that there were significant genotype-related differences in response to albuterol compared with placebo. Patients with the R/R genotype improved when beta-agonist therapy was withdrawn and replaced with ipratropium bromide, whereas those with the G/G genotype did better with regular beta-agonist therapy than when it was withdrawn. Israel et al. (2004) concluded that genotype at amino acid 16 of ADRB2 affects long-term response to albuterol use and that bronchodilator treatments avoiding albuterol may be appropriate for patients with the R/R genotype.
In a metaanalysis of 28 published studies, Contopoulos-Ioannidis et al. (2005) confirmed the association between the gly16 polymorphism and nocturnal asthma, but found no association between the R16G variant and asthma susceptibility overall or bronchial hyperresponsiveness. Tsai et al. (2006) found no association between the R16G polymorphism and asthma diagnosis or asthma-related phenotypes among 264 African American children with asthma.
Large et al. (1997) found that in Sweden the gly16 allele had a frequency of 64% in obese (601665) subjects and 66% in nonobese subjects. This was not a significant difference.
Meirhaeghe et al. (2001) examined the effects of the gly16-to-arg (G16R) ADRB2 polymorphism on circulating nonesterified fatty acid (NEFA) levels. They genotyped a cohort of 604 Caucasian individuals (aged 40 to 65 years) and examined the relationships between genotype, BMI, NEFA, and lipid levels. Women bearing the R16 allele had higher BMI values than G/G women. Women carriers of the R/R genotype had lower fasting plasma NEFAs and greater suppression of NEFAs after an oral glucose load than women bearing the G16 allele. In multivariate analysis after adjustment for age, sex, and smoking status, the interaction between the ADRB2 genotype and BMI in determining fasting NEFA concentrations was statistically significant. The availability of objective measures of total energy expenditure in this population permitted the further examination of interactions, particularly that between genotype and physical activity. In the population as a whole, after adjustment for confounding by age, smoking, and BMI, the effect of the R/R genotype on the suppression of NEFA levels was modified by physical activity level.
In a study of 276 patients with metabolic syndrome (see 605552) and 872 controls, Dallongeville et al. (2003) found odds ratios of metabolic syndrome of 1.83 and 2.43 in men bearing the G16/R16 and R16/R16 genotypes, respectively, in multivariate analyses adjusting for age, physical activity, smoking habits, alcohol consumption, and body mass index. No association was found in women. The authors concluded that the R16 variant of the ADRB2 gene contributes to metabolic syndrome susceptibility in men.
Large et al. (1997) found a significant association between the gln27-to-glu (Q27E) polymorphism of the ADRB2 gene and obesity (601665). The gln27 allele was present in 52% of obese subjects and in 70% of nonobese subjects.
Corbalan et al. (2002) noted that exercise produces an increase in sympathetic nervous system activity, a response that may be impaired by ADRB2 dysfunction. They studied 252 female Spanish subjects to examine the association between obesity risk and the glu27 polymorphism of the ADRB2 gene, depending on physical activity. They found that obese women who are carriers of the glu27 allele do not benefit equally from physical activity compared to noncarriers of the glu27 allele. Corbalan et al. (2002) concluded that the glu27 allele of the ADRB2 gene is a physical activity-dependent factor for obesity risk.
Dewar et al. (1997) reported a significant association between the glutamine-27 ADRB2 polymorphism and elevated IgE levels in families with a history of asthma (600807). Hopes et al. (1998) determined the genotype at amino acid 27 in 425 children between 5 and 15 years of age who visited a hospital emergency room. In this sample, 104 (24%) were found to have asthma. There was a significant excess of the gln27 ADRB2 polymorphism in asthmatic children compared to nonasthmatic controls; after excluding other asthma risk factors, the gln27 allele conferred a 2-fold increase in risk (odds ratio = 2.18, CI = 1.13-4.23, P = 0.02). Conversely, homozygosity for the glu27 allele lowered the asthma risk (odds ratio = 0.46, CI = 0.24-0.89). See also Martinez et al. (1997).
In a metaanalysis of 28 published studies, Contopoulos-Ioannidis et al. (2005) found no association between the Q27E polymorphism and asthma susceptibility overall or bronchial hyperresponsiveness.
In a study of 276 patients with metabolic syndrome (see 605552) and 872 controls, Dallongeville et al. (2003) found odds ratios of metabolic syndrome of 0.99 and 1.67 in men bearing the Q27/E27 and Q27/Q27 genotypes, respectively, in multivariate analyses adjusting for age, physical activity, smoking habits, alcohol consumption, and body mass index. No association was found in women. The authors concluded that the Q27 variant of the ADRB2 gene contributes to metabolic syndrome susceptibility in men.
The frequency of the ile allele of the thr164-to-ile (T164I) polymorphism of the ADRB2 gene is 0.5 to 2.3% (Reihsaus et al., 1993; Xie et al., 2002). The polymorphism has the most profound functional consequences in vitro of all the ADRB2 polymorphisms. In in vivo studies, Dishy et al. (2004) found that the T164I polymorphism was associated with a 5-fold reduction in sensitivity to beta-2-receptor agonist-mediated vasodilation; vasoconstrictor sensitivity was increased. The overall effect of the T164I polymorphism was to shift the balance of adrenergic vascular tone toward vasoconstriction. This suggested a mechanistic explanation for the clinical observation of decreased survival in patients with congestive heart failure heterozygous for the T164I polymorphism.
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