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Differential Desensitization of Homozygous Haplotypes of the ß₂-Adrenergic Receptor in Lymphocytes

Departments of Molecular Pharmacology, Pulmonology, Allergology, and Epidemiology, University of Groningen, Groningen, The Netherlands; and Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Correspondence and requests for reprints should be addressed to Herman Meurs, Ph.D., Department of Molecular Pharmacology, University Center for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713-AV Groningen, The Netherlands. E-mail: h.meurs{at}rug.nl

Single-nucleotide polymorphisms of the ß₂-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 ß₂-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 ß₂-adrenergic receptor sequestration and downregulation were measured in relation to ß₂-adrenergic receptor-mediated inhibition of IFN- and interleukin-5 production. We observed that lymphocytes of individuals bearing the CysGlyGln haplotype were more susceptible to desensitization of the ß-agonist–induced cAMP response than those of individuals with the ArgGlyGlu or CysArgGln haplotype. The haplotype-dependent desensitization of ß-agonist–induced cAMP response was not associated with haplotype-dependent ß₂-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 (CD3/CD28). This is the first study demonstrating haplotype-related differences in agonist-induced ß₂-adrenergic receptor desensitization in primary human cells. This haplotype-related desensitization of the ß₂-adrenergic receptor in lymphocytes might have consequences regarding the regulation of helper T-cell type 2 inflammatory responses.

Key Words: 5' leader cistron • cAMP • cytokine production • sequestration and downregulation • single-nucleotide polymorphism

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