The Ile164 β2-adrenoceptor polymorphism alters salmeterol exosite binding and conventional agonist coupling to Gs

Green, Stuart A.; Rathz, Deborah A.; Schuster, A; Liggett, Stephen B.

doi:10.1016/s0014-2999(01)01049-4

Cited by 90 publications

(67 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…38,40 This functional work on the b 2 AR needs to be expanded to include the promotor and 3' UTR variants newly identified.…”

Section: St Weiss Et Al 314mentioning

confidence: 99%

“…Over the last decade nonsynonymous coding SNPs of the human b 2 AR were identified 37 and characterized in cells by us. [38][39][40][41] Arg or Gly can be found at amino-acid 16, whereas Gln or Glu can be found at position 27. A rare polymorphism Thr164-Ile (5% heterozygous frequency) has also been detected.…”

Section: Asthma Pharmacogenetics To Datementioning

confidence: 99%

“…42,43 The rare Ile164 b 2 AR has decreased agonist affinity, depressed coupling to adenylyl cyclase, and a decreased duration of action (by B50%) in response to the long-acting b 2 -agonist salmeterol. 38,40 This functional work on the b 2 AR needs to be expanded to include the promotor and 3' UTR variants newly identified.…”

Section: Asthma Pharmacogenetics To Datementioning

confidence: 99%

See 2 more Smart Citations

Overview of the pharmacogenetics of asthma treatment

et al. 2006

View full text Add to dashboard Cite

Asthma affects approximately 300 million individuals worldwide. Medications comprise a substantial portion of asthma expenditures. Despite the availability of three primary therapeutic classes of medications, there are a significant number of nonresponders to therapy. Available data, as well as previous pharmacogenetic studies, suggest that genetics may contribute as much as 60-80% to the interindividual variability in treatment response. In this methodologic review, after providing a broad overview of the asthma pharmacogenetics literature to date, we describe the application of a novel family-based screening algorithm to the analysis of pharmacogenetic data and highlight our approach to identifying and verifying loci influencing asthma treatment response. This approach seeks to address issues related to multiple comparisons, statistical power, population stratification, and failure to replicate from which previous population-based or case-control pharmacogenetic association studies may suffer. Identification of such replicable loci is the next step towards the goal of 'individualized therapy' for asthma. The Pharmacogenomics Journal (2006) 6, 311-326. doi:10.1038/sj.tpj.6500387; published online 25 April 2006Keywords: beta-agonist; leukotriene; corticosteroid; FEV 1 ; genetics IntroductionThe goal of this review is to give a comprehensive assessment of asthma pharmacogenetics and highlight the scientific approach being taken by the pharmacogenetics of asthma treatment (PHAT) research group (http:// www.pharmgat.org/) to this research area. Our approach strives to address many of the potential problems inherent in genetic association studies, including those related to multiple comparisons, lack of statistical power, population stratification, and failure to replicate. Moreover, our group of collaborative investigators is well positioned to investigate the molecular biology and functional genomics of identified candidate gene associations. In this review, we will cover some aspects of asthma health care, pathobiology, and review the available pharmacogenetics literature on the important types and pathways of asthma medications: b-agonists, leukotriene (LT) antagonists, methylxanthines, and corticosteroids. We will then present details of our research approach to finding replicated pharmacogenetic associations and suggest what the future may hold for this research area. Pharmacogenetics -definition and rationalePharmacogenetics is the study of the role of genetic determinants in the variable, interindividual response to medications. Numerous examples of heritable differences in pharmacokinetics (drug distribution and metabolism) in The Pharmacogenomics Journal (2006) 6, 311-326 & 2006 Nature Publishing Group All rights reserved 1470-269X/06 $30.00 www.nature.com/tpj individuals resulting in varied clinical response to medications have been described. 1 Other mechanisms underlying the genetic response to drugs includes alterations in pharmacodynamics (changes in the drug target), idiosyncratic associations (unin...

show abstract

“…38,40 This functional work on the b 2 AR needs to be expanded to include the promotor and 3' UTR variants newly identified.…”

Section: St Weiss Et Al 314mentioning

confidence: 99%

Section: Asthma Pharmacogenetics To Datementioning

confidence: 99%

Section: Asthma Pharmacogenetics To Datementioning

confidence: 99%

See 1 more Smart Citation

Overview of the pharmacogenetics of asthma treatment

et al. 2006

View full text Add to dashboard Cite

show abstract

“…[12][13][14][15][16][17][18][19][20][21][22] Finally, the substitution of isoleucine for threonine at codon 164 (Thr164Ile), in the receptor transmembrane-spanning domains, alters agonist binding and decreases coupling of the G s protein to the receptor. 23,24 There is evidence from in vitro studies that some of these receptor variants might be important for catecholamine-induced adipocyte lipolysis in humans. 16,25 Furthermore, polymorphisms in G proteins involved in catecholamine signaling may alter corresponding receptor and hormone function.…”

Section: Introductionmentioning

confidence: 99%

Association of a beta-2 adrenoceptor (ADRB2) gene variant with a blunted in vivo lipolysis and fat oxidation

et al. 2006

View full text Add to dashboard Cite

Background and aims: Obesity is associated with a blunted b-adrenoceptor-mediated lipolysis and fat oxidation. We investigated whether polymorphisms in codon 16, 27 and 164 of the b 2 -adrenoceptor gene (ADRB2) and exon 10 of the G protein b 3 -subunit gene (GNB3) are associated with alterations in in vivo lipolysis and fat oxidation. Design and methods: Sixty-five male and 43 female overweight and obese subjects (body mass index (BMI) range: 26.1-48.4 kg/m 2 ) were included. Energy expenditure (EE), respiratory quotient (RQ), circulating free fatty acid (FFA) and glycerol levels were determined after stepwise infusion of increasing doses of the non-selective b-agonist isoprenaline (ISO). Results: In women, the Arg16 allele of the ADRB2 gene was associated with a blunted increase in circulating FFA, glycerol and a decreased fat oxidation during ISO stimulation. In men, the Arg16 allele was significantly associated with a blunted increase in FFA but not in glycerol or fat oxidation. Conclusion: These results suggest that genetic variation in the ADRB2 gene is associated with disturbances in in vivo b-adrenoceptor-mediated lipolysis and fat oxidation during b-adrenergic stimulation in overweight and obese subjects; these effects are influenced by gene-gender interactions.

show abstract

“…More recently, the focus has shifted to include alterations in drug target genes. 9 Polymorphisms affecting drug sensitivity have been suggested in inositol polyphosphate-1-phosphatase (INPP1), 10 the b2-adrenoceptor (ADRB2) 11 and the serotonin 2A receptor (5HTR2A). 12 Identification of polymorphisms that affect efficacy and adverse event susceptibility have the potential to impact selection of patient populations, dosage and formulation.…”

Section: Introductionmentioning

confidence: 99%

Identification of single-nucleotide polymorphisms of the human neurokinin 1 receptor gene and pharmacological characterization of a Y192H variant

Randolph¹,

Simon²,

Arreaza³

et al. 2004

Pharmacogenomics J

View full text Add to dashboard Cite

Neurokinin receptors in the central nervous system are involved in the neural circuitry of anxiety, depression and emesis. This has led to the development of nonpeptidic NK1 receptor antagonists as therapeutic agents. Clinical trials have shown that NK1 receptor antagonists have efficacy in chemotherapyinduced emesis and depression. Sequence polymorphisms can potentially influence the efficacy of drugs in patient populations and are an important consideration in the drug development process. To identify DNA sequence variants in the NK1 receptor, comparative DNA sequencing was performed on a population of 93 individuals. In total, 19 single-nucleotide polymorphisms (SNPs) were identified with one SNP (g.78351T4C) resulting in a tyrosine to histidine subsitution at residue 192 (Y192H). The Y192H variant was expressed using site-directed mutagenesis and was characterized with respect to affinity, receptor kinetics, functional calcium response and receptor internalization. In all cases the Y192H variant was found to display properties similar to those of the wild-type receptor.

show abstract

The Ile164 β2-adrenoceptor polymorphism alters salmeterol exosite binding and conventional agonist coupling to Gs

Cited by 90 publications

References 26 publications

Overview of the pharmacogenetics of asthma treatment

Overview of the pharmacogenetics of asthma treatment

Association of a beta-2 adrenoceptor (ADRB2) gene variant with a blunted in vivo lipolysis and fat oxidation

Identification of single-nucleotide polymorphisms of the human neurokinin 1 receptor gene and pharmacological characterization of a Y192H variant

Contact Info

Product

Resources

About