Disease relevance of ADRB1

• CONCLUSIONS: This is the first study to investigate the relationship between the Gly389Arg ADRB1 variant and obesity [1].
• These data also suggest that blocking ADRB-mediated angiogenesis could have therapeutic implications for the management of ovarian cancer [2].
• METHODS AND RESULTS: Patients with essential hypertension and echocardiographically diagnosed LVH were included in a double-blind study to receive treatment with either the angiotensin II type 1 receptor (AT1-receptor) antagonist irbesartan (n = 41), or the beta-1 adrenergic receptor blocker atenolol (n = 43) as monotherapy for 3 months [3].
• A substantial body of evidence suggests involvement of the human beta1-adrenoceptor (beta1-AR) gene in the pathophysiology of dilated cardiomyopathy (DCM), a severe heart disease of significant public health impact [4].
• We investigated associations of ADRB polymorphisms with open-angle glaucoma (OAG), because ADRB gene polymorphisms alter receptor function [5].

Psychiatry related information on ADRB1

• A polymorphism of the beta1-adrenergic receptor is associated with low extraversion [6].
• CONCLUSIONS: The lack of difference between propranolol and betaxolol suggests that beta 1-adrenoceptor blockade is sufficient to improve neuroleptic-induced akathisia [7].
• Metoprolol, a selective beta 1-adrenoreceptor blocker, was administered to two patients with intermittent explosive disorder who had not done well with previous medications, including propranolol and carbamazepine [8].
• These data indicate that a disruption of beta 1-adrenoceptor-G protein coupling occurs in the temporal cortex of Alzheimer's disease patients [9].
• Repeated electroconvulsive shock prevents increased neocortical beta 1-adrenoceptor binding after DSP-4 treatment in rats [10].

High impact information on ADRB1

• These results unambiguously prove that T. cruzi is able to induce a functional autoimmune response against the cardiovascular human beta 1-adrenergic receptor through a molecular mimicry mechanism [11].
• Molecular mimicry between the immunodominant ribosomal protein P0 of Trypanosoma cruzi and a functional epitope on the human beta 1-adrenergic receptor [11].
• Subcutaneous abdominal adipose tissue of healthy non-obese subjects was microdialyzed with equimolar concentrations of dobutamine (selective beta 1-adrenoceptor agonist), terbutaline (selective beta 2-adrenoceptor agonist), or CGP 12177 (selective beta 3-adrenoceptor agonist) [12].
• In these same nonfailing and failing left ventricles the respective beta 1-adrenergic receptor densities were 67.9 +/- 6.9 fmol/mg vs. 29.6 +/- 3.5 fmol/mg (P = 0.0001) [13].
• Mapping of a functional autoimmune epitope on the beta 1-adrenergic receptor in patients with idiopathic dilated cardiomyopathy [14].

Chemical compound and disease context of ADRB1

• METHODS: Patients with mild-to-moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind study to receive treatment with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan (n = 43), or the beta1-adrenergic receptor blocker atenolol (n = 43) [15].
• The basal lipolysis factor was significantly (P less than 0.006) decreased 31% with endotoxin. beta-1 adrenergic receptor stimulation (isoproterenol, 1 X 10(-8) to 1 X 10(-4) M) was significantly decreased an average of 31% with E. coli endotoxin [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].
• In vivo in 10 healthy volunteers isoprenaline-induced tachycardia was antagonized with equal potency by the beta-2 adrenoceptor-selective antagonist ICI 118,551 and the beta-1 adrenoceptor-selective antagonist bisoprolol indicating that it is mediated by cardiac beta-1 and beta-2 adrenoceptor stimulation to about the same degree [18].
• 4. In the presence of a beta 1-adrenoceptor agonist, as assessed by reduction of exercise tachycardia, increasing doses of celiprolol produced significantly less beta 1-adrenoceptor blockade compared with atenolol [19].

Biological context of ADRB1

• An AA genotype at bp 145 in ADRB1 was also associated with higher resting SBP and DBP than AG or GG genotypes (P < 0.03) [20].
• The distal long arm of chromosome 10 harbors genes of biomedical interest such as MXI1, a putative tumor suppressor gene, and those encoding the adrenergic receptors alpha2A (ADRA2A) and beta1 (ADRB1) [21].
• Genetics linked to a defined pathology and its corresponding drug therapies is exemplified by ADRB1, ACE, CETP and APOE and drug response in metabolic syndrome [22].
• RNA blot analysis indicates a message of 2.5 kilobases in rat tissues, with a pattern of tissue distribution consistent with beta 1AR binding [23].
• Resistance of the human beta 1-adrenergic receptor to agonist-mediated down-regulation. Role of the C terminus in determining beta-subtype degradation [24].

Anatomical context of ADRB1

• PURPOSE: The human trabecular meshwork and ciliary body, which express beta-adrenergic receptors (ADRB1 and ADRB2), control aqueous humor dynamics [5].
• At low (-)-epinephrine concentrations, contractile responses are predominantly mediated by beta 2AR rather than beta 1AR in myocytes from failing hearts [25].
• Expression of receptor protein in Xenopus laevis oocytes conveys adenylate cyclase responsiveness to catecholamines with a typical beta 1AR specificity [23].
• G protein-coupled receptors such as the beta1-adrenergic receptor (beta1AR) must be trafficked to the plasma membrane in order to bind with their extracellular ligands and regulate cellular physiology [26].
• Both Chinese hamster fibroblast and 293 cells demonstrate receptor-specific desensitization of the beta 1 AR within 3-5 min [27].

Associations of ADRB1 with chemical compounds

• When 300 nmol/L CGP 20712A was present as the sole antagonist, only a marginal shift of the concentration-response curve for (-)-epinephrine was usually observed, indicating that beta 1AR were not mediating the effect of these low concentrations of (-)-epinephrine [25].
• Accordingly, we used the proline-rich third intracellular loop of the beta1-AR either as a glutathione S-transferase fusion protein in biochemical "pull-down" assays or as bait in the yeast two-hybrid system to search for interacting proteins [28].
• Several G-protein coupled receptors, such as the beta1-adrenergic receptor (beta1-AR), contain polyproline motifs within their intracellular domains [28].
• Direct binding of the beta1 adrenergic receptor to the cyclic AMP-dependent guanine nucleotide exchange factor CNrasGEF leads to Ras activation [29].
• This epitope could be identified as a polyanionic stretch present in the second extracellular loop of both the beta1-adrenoceptor and the M2 acetylcholine receptor [30].
• Ethnic differences in sensitivity to atenolol remained significant (P=0.006) after adjustment for beta1-AR and alpha2C-AR genotypes [31].

Physical interactions of ADRB1

• Using the beta1-adrenergic receptor carboxyl terminus as bait, we identified the novel beta1-adrenergic receptor-binding partner GIPC in a yeast two-hybrid screen of a human heart cDNA library [32].
• 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 [33].
• Because DIO2 is activated through a beta-adrenergic receptor-dependent pathway, we further hypothesized that variation in the ADRB genes interacts with DIO2 Thr92Ala variant to influence metabolic traits [34].
• The sera of patients with myocarditis and idiopathic dilated cardiomyopathy contain agonistic autoantibodies that bind to the beta 1-adrenoceptor [35].

Regulatory relationships of ADRB1

• Interaction with cystic fibrosis transmembrane conductance regulator-associated ligand (CAL) inhibits beta1-adrenergic receptor surface expression [26].
• Consistent with a GRK mechanism, receptor-specific desensitization of the beta 1AR was enhanced by overexpression of beta-arrestin-1 and -2 in transfected 293 cells [27].
• 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) [36].
• These data suggest that GIPC can regulate beta1-adrenergic receptor-stimulated, Gi-mediated, ERK activation while having no effect on receptor internalization or Gs-mediated cAMP signaling [32].
• G protein-coupled receptor kinase 5 regulates beta 1-adrenergic receptor association with PSD-95 [37].

Other interactions of ADRB1

• 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 [23].
• We conclude that rapid agonist-induced desensitization of the beta 1AR involves phosphorylation of the receptor by both PKA and at least beta ARK1 in intact cells [27].
• We found that the GNB3 T allele produces a significant risk for AD in individuals homozygous for the ADRB1 C allele, suggesting that the combined effect of both polymorphisms influences AD susceptibility [38].
• SR 59119A, salbutamol, and isoproterenol (ADRB3, ADRB2, and nonselective ADRB agonists, respectively) induced a concentration-dependent relaxation of placental artery rings obtained from women with uncomplicated or preeclamptic pregnancies [39].
• Identification of the endophilins (SH3p4/p8/p13) as novel binding partners for the beta1-adrenergic receptor [28].

Analytical, diagnostic and therapeutic context of ADRB1

• Pulsed field gel electrophoresis has shown that the alpha 1- and beta 2-AR genes in humans are within 300 kilobases (kb) and the distance between the alpha 2- and beta 1-AR genes is less than 225 kb [40].
• The enzyme immunoassays and the SPR studies on the anti-beta1 adrenoceptor and the M2 acetylcholine receptor autoantibodies were dependent on the ionic strength of the interaction buffer, suggesting the importance of electrostatic interactions in Ab recognition [30].
• Agonist-induced beta 1AR desensitization in 293 cells correlates with a 2 +/- 0.3-fold increase in phosphorylation of the beta 1AR, determined by immunoprecipitation of the beta 1AR from cells metabolically labeled with 32P(i) [27].
• This study investigated the relation between the severity of heart failure and the extent of the reduction of beta 1-adrenergic receptor messenger ribonucleic acid (mRNA) levels in biopsy specimens from the ventricular septum obtained during cardiac catheterization of patients with various degrees of heart failure [41].
• Patients with coronary vasculopathy (CVP) after cardiac transplantation had lower absolute numbers of beta 1-AR compared with patients without CVP [42].

References