Chong L K, Chowdry J, Ghahramani P, Peachell P T
Section of Molecular Pharmacology and Pharmacogenetics, University of Sheffield, The Royal Hallamshire Hospital, UK.
Pharmacogenetics. 2000 Mar;10(2):153-62. doi: 10.1097/00008571-200003000-00007.
The beta-adrenoceptor agonist, isoprenaline, inhibited the immunoglobulin E-mediated release of histamine from human lung mast cells (HLMC). Long-term (24 h) exposure of HLMC to isoprenaline reduced the subsequent effectiveness of isoprenaline to inhibit histamine release. The extent of this functional desensitization was variable with some HLMC preparations resistant and others highly susceptible. We sought to determine whether the variability in the degree of functional desensitization was influenced by genetic polymorphisms in the beta2-adrenoceptor. HLMC preparations were genotyped at two polymorphic loci, positions 16 (arg to gly) and 27 (gln to glu), and the effect of desensitizing conditions (24 h with 10(-6) M isoprenaline) on the subsequent ability of isoprenaline (10(-7) M) to inhibit histamine release from HLMC was determined (n = 72). In HLMC preparations expressing beta2-adrenoceptors with arg (wild-type) or gly (mutant) at position 16, desensitization was 71 +/- 5% (n = 18) or 43 +/- 5%, (n = 26), respectively, whereas the desensitization was 59 +/- 6% (n = 28) for heterozygotes at this position. In HLMC preparations expressing beta2-adrenoceptors with gln (wild-type) or glu (mutant) at position 27, desensitization was 65 +/- 5% (n = 25) or 28 +/- 7% (n = 17), respectively, whereas the desensitization was 61 +/- 5% (n = 30) for heterozygotes at this position. These data suggest that mutant (gly16 and glu27) forms of the receptor are resistant to desensitization compared to wild-type (arg16 and gln27) forms. However, analyses to determine the relative contributions of positions 16 and 27 suggest that position 27 is more important in influencing the degree of functional desensitization.
β-肾上腺素能受体激动剂异丙肾上腺素可抑制免疫球蛋白E介导的人肺肥大细胞（HLMC）组胺释放。HLMC长期（24小时）暴露于异丙肾上腺素会降低其随后抑制组胺释放的效果。这种功能脱敏的程度存在差异，一些HLMC制剂具有抗性，而另一些则高度敏感。我们试图确定功能脱敏程度的差异是否受β2-肾上腺素能受体基因多态性的影响。对HLMC制剂在两个多态性位点（第16位（精氨酸突变为甘氨酸）和第27位（谷氨酰胺突变为谷氨酸））进行基因分型，并确定脱敏条件（10^(-6) M异丙肾上腺素处理24小时）对随后异丙肾上腺素（10^(-7) M）抑制HLMC组胺释放能力的影响（n = 72）。在第16位表达具有精氨酸（野生型）或甘氨酸（突变型）的β2-肾上腺素能受体的HLMC制剂中，脱敏率分别为71±5%（n = 18）或43±5%（n = 26）；而该位点杂合子的脱敏率为59±6%（n = 28）。在第27位表达具有谷氨酰胺（野生型）或谷氨酸（突变型）的β2-肾上腺素能受体的HLMC制剂中，脱敏率分别为65±5%（n = 25）或28±7%（n = 17）；而该位点杂合子的脱敏率为61±5%（n = 30）。这些数据表明，与野生型（精氨酸16和谷氨酰胺27）形式相比，受体的突变型（甘氨酸16和谷氨酸27）形式对脱敏具有抗性。然而，确定第16位和第27位相对贡献的分析表明，第27位在影响功能脱敏程度方面更为重要。
