None of the isoforms exhibited significant co-localization with the recycling endosome marker Rab11 in response to isoproterenol treatment. Confocal microscopy revealed that the receptor isoforms had similar co-localization with the early endosomal marker EEA1 following isoproterenol treatment, suggesting that they had similar patterns of internalization. Consistent with these differences in down-regulation between isoforms, prolonged isoproterenol treatment resulted in diminished cyclic AMP response to subsequent isoproterenol challenge in β 2AR-RE relative to β 2AR-GE. Ligand binding assays demonstrated that after 24 h exposure to 1 μM isoproterenol, isoforms with Arg16 (β 2AR-RE and β 2AR-RQ) underwent increased down-regulation compared to isoforms with Gly16 (β 2AR-GE and β 2AR-GQ). The functional consequences of the four possible combinations of these polymorphisms in the human β 2AR (designated β 2AR-RE, -GE, -RQ and -GQ) were studied using site-directed mutagenesis and recombinant expression in HEK 293 cells. We hypothesized that polymorphisms at amino acids 16 and 27 result in differential trafficking and down-regulation of β 2AR variants following β-agonist exposure. Clinical studies suggest that amino-terminal polymorphisms of the β 2AR may act as disease modifiers. The β 2-adrenergic receptor (β 2AR) is an important target for respiratory and cardiovascular disease medications.
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