Influence of genetic polymorphisms in the ??2-adrenoceptor on desensitization in human lung mast cells

Abstract

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.

Association of β2 adrenergic receptor polymorphisms and related haplotypes with triglyceride and LDL-cholesterol levels

“…9 Rather conflicting results have been published on the ex vivo agonist promoted desensitization of these b 2 -AR isoforms. Chong et al 38 found that both mutant forms (Gly16 and Glu27) of the b 2 -AR were resistant to isoprenaline-induced desensitization compared to wild-type forms (Arg16 and Gln27), while an opposite result was also reported. 12 These alterations may be due to a different mechanism considering that ligand binding and functional activation of these receptors were not affected.…”

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

“…522 the Gly16 genotype exhibited greater agonist-induced desensitization in human airway smooth muscle cells (Table 7) (Moore et al, 2000), although that was not confirmed in a study on human lung mast cells (Table 7) (Chong et al, 2000). Likewise, a greater agonist-induced desensitization was reported for the Glu27 variant in human airway smooth muscle cells (Moore et al, 2000), whereas less desensitization was found for the same genotype in human lung mast cells (Table 7) (Chong et al, 2000). These data suggest the possibility that the effects of these SNPs in the amino terminus of the ␤ 2 -AR may depend on the cell type in which it is expressed.…”

Overview of the pharmacogenetics of asthma treatment

“…41 However, when other end points were utilized the phenotypes were not always as would have been predicted from the transfected cell data. 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.…”

“…42,43 The rare Ile164 b 2 AR has decreased agonist affinity, depressed coupling to adenylyl Overview of the pharmacogenetics of asthma treatment…”