Polymorphism of the beta(2)-adrenergic receptor gene and desensitization in human airway smooth muscle

We examined the Influence of two common polymorphic forms of the beta (2)-a drenergic receptor (beta (2)AR): the Gly16 and Glu27 alleles, on acute and long-term beta (2)AR desensitization in human airway smooth muscle (HASM) c ells. In cells from 15 individuals, considered without respect to genotype, pretreatment with Isoproterenol (ISO) at 10(-7) M for 1 h or 24 h caused a pproximately 25% and 64% decreases in the ability of subsequent ISO (10(-6) M) stimulation to reduce HASM cell stiffness as measured by magnetic twist ing cytometry. Similar results were obtained with ISO-induced cyclic adenos ine monophosphate (cAMP) as the outcome indicator. Data were then stratifie d post hoc by genotype. Cells containing at least one Glu27 allele (equival ent to presence of the Gly16Glu27 haplotype) showed significantly greater a cute desensitization than did cells with no Glu27 allele, whether ISO-induc ed cell stiffness (34% versus 19%, p < 0.03) or cAMP formation (58% versus 11%, p < 0.02) was measured. Likewise, cells with any Glu27 allele showed g reater long-term desensitization of cell stiffness and cAMP formation respo nses than did cells without the Glu27 allele. The distribution of genotypes limited direct conclusions about the influence of the Gly16 allele. Howeve r, presence of the Gly16Gln27 haplotype was associated with less acute and long-term desensitization of ISO-induced cAMP formation than was seen in ce lls without the Gly16Gln27 haplotype (14% versus 47%, p < 0.09 for short-te rm desensitization; 32% versus 84%, p < 0.01 for longterm desensitization), suggesting that the influence of Glu27 is not through its association with Gly16. The Glu27 allele was in strong linkage disequilibrium with the Arg1 9 allele, a polymorphic: form of the beta (2)AR upstream peptide of the 5'- leader cistron of the beta (2)AR, and this polymorphism in the beta (2)AR 5 '-flanking region may explain the effects of the Glu27 allele. Cells with a ny Arg19 allele showed significantly greater acute and long-term desensitiz ation of ISO-induced cAMP formation than did cells without the Arg19 allele (54% versus 2%, p < 0.01 for short-term desensitization; 73% versus 35% p < 0.05 for long-term desensitization). Similar results were obtained for IS O-induced changes in cell stiffness. Thus, the presence of the Glu27 allele is associated with increased acute and long-term desensitization in HASM.