Disease relevance of ADRB2

• CONCLUSIONS : From our present analysis we conclude that the ADRB2 gene polymorphisms studied do not contribute in any important way to the risk of essential hypertension or MI in subjects of European ancestry [1].
• We investigated whether genetic variation of the ADRB2 gene might be related to essential hypertension or myocardial infarction (MI) [1].
• CONCLUSIONS: Variants of the ADRB2, ADRA1d and IL-4 genes may be related to a predisposition to interstitial cystitis [2].
• OBJECTIVE: To assess the effects of a polymorphism in codon 16 (Arg16-->Gly) of the ADRB2 gene, which has been associated with a decrease in beta2-receptor density and efficiency, on longitudinal changes in obesity from childhood to young adulthood in a biracial cohort [3].
• CONCLUSION: Only variations in the ADRB2 gene and LEPR gene, may contribute to susceptibility to weight gain [4].

Psychiatry related information on ADRB2

• The 27Glu polymorphism of the beta2-adrenergic receptor gene interacts with physical activity influencing obesity risk among female subjects [5].
• We genotyped 202 female subjects and examined the relationships between three major ADRB2 haplotypes and psychological factors, resting blood pressure, and the risk of developing a chronic musculoskeletal pain condition-Temporomandibular Joint Disorder (TMD) [6].
• Neutrophil beta2-adrenergic receptor coupling efficiency to Gs protein in subjects with post-traumatic stress disorder and normal controls [7].
• Panic attacks are associated with increased autonomic symptoms, suggesting increased beta 2-adrenergic receptor (beta 2AR) function in PD [8].
• Abnormal beta2-adrenergic receptor coupling to Gs protein is implicated in depressive disorders [9].

High impact information on ADRB2

• A dose-response curve of the effect of the beta2-adrenergic-receptor agonist isoproterenol was constructed (dose range, 4 to 480 ng per minute) [10].
• We studied the effects of two common polymorphisms of the beta2-adrenergic receptor, one at codon 16 and one at codon 27, on agonist-mediated vasodilatation and desensitization in the vascular bed [10].
• The role of long-acting beta2-adrenergic-receptor agonists, such as salmeterol, needs to be defined [11].
• Identification of a Gs activator region of the beta 2-adrenergic receptor that is autoregulated via protein kinase A-dependent phosphorylation [12].
• We have localized a G protein activator region of the human beta 2-adrenergic receptor to region beta III-2 (from Arg259 to Lys273) [12].

Chemical compound and disease context of ADRB2

• This study examined whether the therapeutic efficacy of benazepril on essential hypertension is modified by beta2 adrenergic receptor gene (ADRB2) Arg16Gly (R16G) polymorphism [13].
• Permeabilization of human epidermoid carcinoma A431 cells with digitonin was used to permit access of the charged inhibitors to the cytosol; this procedure did not interfere with the pattern of isoproterenol-induced homologous desensitization of beta 2AR-stimulated adenylyl cyclase [14].
• Since beta2 adrenergic receptor-mediated effects such as hypokalemia were found only at infusion rates > or = 3 microg/kg/min, the effects of dopexamine at infusion rates < 3 microg/kg/min may be mainly mediated by stimulation of dopaminergic receptors and the indirect sympathomimetic action [15].
• CONCLUSIONS: The Gly16 mutation of the beta2-adrenoceptor gene is associated with increased insulin resistance, adiposity, and BP accompanied by higher plasma NE levels early in the metabolic disease in developing obesity [16].
• Disodium cromoglycate affected neither the rightward shift of beta 2-adrenoceptor-mediated responses nor the small rightward shift in beta 1-adrenoceptor-mediated exercise tachycardia after 2 weeks' administration of terbutaline [17].

Biological context of ADRB2

• The beta(2)AR genotypes at codons 16 and 27 of ADRB2 were determined [18].
• OBJECTIVES: Our aim was to measure bronchodilator response in patients with asthma stratified by ADRB2 haplotype [19].
• CONCLUSIONS: Genetic variation of the ADRB2 does not influence the immediate response to inhaled beta2-agonist [19].
• Polymorphisms of the ADRB2 gene have been shown to be potentially related to essential hypertension and other non-cardiovascular disease phenotypes [1].
• At bp 46 in ADRB2, GG homozygotes had higher resting DBP than subjects possessing any A allele (P < 0.05) [20].

Anatomical context of ADRB2

• BACKGROUND: The beta2-adrenergic receptor (ADRB2) plays a major role in regulating energy expenditure by stimulating lipid metabolism in human adipose tissue [3].
• PURPOSE: The human trabecular meshwork and ciliary body, which express beta-adrenergic receptors (ADRB1 and ADRB2), control aqueous humor dynamics [21].
• The phosphoprotein EBP50 (for ezrinradixin-moesin(ERM)-binding phosphoprotein-50) binds to the cytoplasmic tail of the beta2-adrenergic receptor through a PDZ domain and to the cortical actin cytoskeleton through an ERM-binding domain [22].
• The most common response in single myocytes was that ICI 118,551 (50 nmol/L) shifted the concentration-response curve less than 10-fold: this was lower than the 100-fold shift expected for a pure beta 2AR effect [23].
• Although beta-arrestins dissociate from some receptors at the plasma membrane, such as the beta2 adrenergic receptor, they remain associated with other GPCRs and internalize with them into endocytic vesicles [24].

Associations of ADRB2 with chemical compounds

• These effects are mediated primarily through activation of the tumor cell cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway by the beta(2) adrenergic receptor (encoded by ADRB2) [25].
• CONCLUSION: Our family-based study provided the first evidence that ADRB2 R16G polymorphism may play an important role in DBP response to benazepril treatment, although the magnitude of the effect appears to be modified by other risk factors such as plasma lipid and glucose profiles [13].
• The ADRB2 Glu27Glu subjects had lower plasma glycerol levels (P = 0.026), while plasma triglycerides (P <0.001) and the insulin:glucose ratio were higher (P = 0.046) as compared to the Gln27Gln group along the peak oxygen consumption trial intervention [26].
• Concentration-response curves to (-)-epinephrine were constructed in the presence and absence of selective antagonists for beta 1 AR (CGP 20712A) and beta 2 AR (ICI 118,551) [23].
• For the beta 2AR, this cysteine has been shown to be important for stimulatory G protein (Gs) coupling and agonist-promoted desensitization [27].

Physical interactions of ADRB2

• The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of the beta2-adrenergic receptor and plays a role in adrenergic regulation of Na+/H+ exchange [28].
• Thus, the function of this cytoplasmic palmitoylcysteine is distinctly different between the alpha 2AR and other G-protein-coupled receptors such as the beta 2AR and rhodopsin, and this suggests that this molecular attribute may subserve diverse roles among members of this family of receptors [27].
• c-Src tyrosine kinase binds the beta 2-adrenergic receptor via phospho-Tyr-350, phosphorylates G-protein-linked receptor kinase 2, and mediates agonist-induced receptor desensitization [29].
• Thus, manipulation of the 1-benzyl moiety of trimetoquinol (1) has resulted in analogs that exhibit potent beta 2-AR binding affinity and significantly lower beta 1-AR and TP receptor affinities [30].
• Protein kinase A regulates AKAP250 (gravin) scaffold binding to the beta2-adrenergic receptor [31].

Enzymatic interactions of ADRB2

• Members of the G protein-coupled receptor kinase family that phosphorylate the beta2-adrenergic receptor facilitate sequestration [32].
• Insulin-like growth factor-I receptor as well as the insulin receptor displays the capacity to phosphorylate the beta 2-adrenergic receptor in vitro, establishing a new paradigm, i.e. G-protein-linked receptors acting as substrates for intrinsic tyrosine kinase growth factor receptors [33].
• Using a mixed micelle assay, GRK2 (beta ARK1) was found to require phospholipid in order to phosphorylate the beta 2-adrenergic receptor [34].

Regulatory relationships of ADRB2

• Beta arrestin-recruited PDE4D5 desensitizes isoprenaline-stimulated PKA phosphorylation of the beta2-AR and the consequential switching of its signaling to ERK [35].
• Beta 2-adrenergic receptor agonist induces IL-18 production without IL-12 production [36].
• The IL-1 alpha-induced increase in beta 2 AR density in confluent cells was antagonized in a concentration-dependent manner by a recombinant protein antagonist of type I IL-1 receptors (IC50: 0.2 nM) [37].
• These results suggest an essential role for ARF proteins in regulating beta2-adrenergic receptor endocytosis [38].
• Cells expressing the wild-type beta 2AR stimulated adenylyl cyclase in response to the agonist isoproterenol with an EC50 approximately 5-fold lower than that observed with the beta 1AR (0.53 +/- 0.14 versus 2.47 +/- 0.52 nM, p < 0.01) [39].

Other interactions of ADRB2

• The 2.4-kilobase cDNA for the human beta 1AR encodes a protein of 477 amino acid residues that is 69% homologous with the avian beta AR but only 54% homologous with the human beta 2AR [40].
• A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins [28].
• GRK6, overexpressed in Sf9 insect cells using the baculovirus system, was able to phosphorylate both the beta 2-adrenergic receptor and rhodopsin in a stimulus-dependent fashion, although it was significantly less active then beta ARK on these substrates [41].
• Identification of the G protein-coupled receptor kinase phosphorylation sites in the human beta2-adrenergic receptor [42].
• RT-PCR was performed on RNA obtained from 23 different human tissues, using primers for the beta 3AR, the beta 2AR, and beta-actin, which acted as a control [43].

Analytical, diagnostic and therapeutic context of ADRB2

• METHODS : Four ADRB2 gene polymorphisms C19R (T-47C), T-20C, G16R (G+46A), Q27E (C+79G) were investigated in two studies: PEGASE, a study of moderate to severe hypertension (707 cases) conducted in France, and ECTIM, a case-control study of MI (1178 cases, 1187 controls) conducted in France, Northern Ireland and Scotland [1].
• RESULTS: The distribution of the genotype frequencies of ADRB2 + 79 C/G was significantly different between the COPD and the control groups in the Egyptians (p = 0.002) [44].
• In conclusion, ADRB2 Arg16Gln27 haplotype may significantly increase the risk of adverse outcomes in patients with HF receiving contemporary HF pharmacotherapy [45].
• ADRB2 polymorphisms and asthma susceptibility: transmission disequilibrium test and meta-analysis [46].
• Polymorphisms in the ADRB2 gene have been associated with obesity and various weight-related traits in cross-sectional studies of adults, but little is known about the effects of the ADRB2 gene on childhood obesity or the propensity to gain weight over time [3].

References