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The effect of β‐agonist on expression and trafficking of β 2 ‐adrenergic receptors with N‐terminal polymorphisms
Author(s) -
Koryakina Yulia A,
Jones Stacie M,
Kurten Richard C,
Cornett Lawrence E
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.748.9
Subject(s) - agonist , receptor , gene isoform , downregulation and upregulation , endocrinology , chemistry , stimulation , medicine , hek 293 cells , microbiology and biotechnology , biology , gene , biochemistry
The β 2 ‐Adrenergic receptor (β 2 AR) is an important target for asthma medications. Stimulation of β 2 AR by agonist inhibits contractile processes and results in bronchodilation. Studies suggest that polymorphisms of the β 2 AR may act as disease modifiers. We hypothesized that polymorphisms at positions 16 and 27 result in differential expression and trafficking of β 2 AR following β‐agonist exposure. The functional consequences of these polymorphisms of the β 2 AR were studied using site‐directed mutagenesis and recombinant expression in HEK293 cells. No differences in receptor density were noted between isoforms after 20 min or 2 h isoproterenol (ISO) treatment in ligand binding assays. However, after 24 h exposure to 1μM ISO, isoforms with Arg16 underwent increased downregulation or reduced receptor density (50.6±2.9% and 70.2±1.7% for R16Q27 and R16E27, respectively) compared to isoforms with Gly16 (27.7±4.2 and 23.2±5.4% for G16Q27 and G16E27, respectively). However, there was no difference between isoforms in co‐localization with Lamp1 (a lysosomal marker) in untreated cells and cells treated with ISO for 24 h. These findings are consistent with an inhibition of β 2 AR recycling by the Arg16 polymorphism. These results may contribute to understanding the genotype‐specific differences in humans in response to β‐agonist therapy. Support has been provided in part by the Arkansas Biosciences Institute.