title: Differential desensitization of homozygous haplotypes of the beta2-adrenergic receptor in lymphocytes.
abstract: Single-nucleotide polymorphisms of the beta(2)-adrenergic receptor gene and its 5' promoter have been associated with differences in receptor function and desensitization. Linkage disequilibrium may account for inconsistencies in reported effects of isolated polymorphisms. Therefore, we have investigated the three most common homozygous haplotypes of the beta(2)-adrenergic receptor (position 19 [Cys/Arg] of the 5' leader cistron and positions 16 [Arg/Gly] and 27 [Gln/Glu] of the receptor) for putative differences in agonist-induced desensitization. Lymphocytes of well defined nonasthmatic, nonallergic subjects homozygous for the haplotype CysGlyGln, ArgGlyGlu, or CysArgGln were isolated. Desensitization of (-)-isoproterenol-induced cyclic adenosine monophosphate (cAMP) accumulation and beta(2)-adrenergic receptor sequestration and downregulation were measured in relation to beta(2)-adrenergic receptor-mediated inhibition of IFN-gamma and interleukin-5 production. We observed that lymphocytes of individuals bearing the CysGlyGln haplotype were more susceptible to desensitization of the beta-agonist-induced cAMP response than those of individuals with the ArgGlyGlu or CysArgGln haplotype. The haplotype-dependent desensitization of beta-agonist-induced cAMP response was not associated with haplotype-dependent beta(2)-adrenergic receptor sequestration or downregulation. In addition, our data suggest reduced inhibition, in lymphocytes of subjects with the CysGlyGln haplotype, of interleukin-5 production induced by treatment with antibodies to the T-cell receptor-CD3 complex and to costimulatory molecule CD28 (alphaCD3/alphaCD28). This is the first study demonstrating haplotype-related differences in agonist-induced beta(2)-adrenergic receptor desensitization in primary human cells. This haplotype-related desensitization of the beta(2)-adrenergic receptor in lymphocytes might have consequences regarding the regulation of helper T-cell type 2 inflammatory responses.
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostendorp
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.forename: Haukeline
authors.initials: H
authors.lastname: Volders
authors.forename: Hajo
authors.initials: H
authors.lastname: Jongepier
authors.forename: Henk F
authors.initials: HF
authors.lastname: Kauffman
authors.forename: H Marike
authors.initials: HM
authors.lastname: Boezen
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Meyers
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Bleecker
authors.forename: S Adriaan
authors.initials: SA
authors.lastname: Nelemans
authors.forename: Johan
authors.initials: J
authors.lastname: Zaagsma
authors.forename: Herman
authors.initials: H
authors.lastname: Meurs
mesh_terms: D000328:Adult; D001120:Arginine; D000242:Cyclic AMP / Q000235:genetics / Q000276:immunology; D003545:Cysteine; D016207:Cytokines / Q000276:immunology; D003888:Desensitization, Immunologic; D015536:Down-Regulation; D005260:Female; D018698:Glutamic Acid; D005973:Glutamine; D005998:Glycine; D006239:Haplotypes / Q000235:genetics / Q000276:immunology*; D006720:Homozygote; D006801:Humans; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000276:immunology; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
chemical_list: D016207:Cytokines; D018343:Receptors, Adrenergic, beta-2; D005973:Glutamine; D018698:Glutamic Acid; D001120:Arginine; D000242:Cyclic AMP; D003545:Cysteine; D005998:Glycine