Journal
PHARMACOGENETICS AND GENOMICS
Volume 18, Issue 8, Pages 729-732Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FPC.0b013e32830967e9
Keywords
asthma; beta-agonist; desensitization; kinases; polymorphism; tachyphylaxis
Funding
- NHLBI NIH HHS [U01 HL065899-05, U01 HL065899, HL 065899] Funding Source: Medline
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Beta-agonist treatment of asthma displays substantial interindividual variation, which has prompted polymorphism discovery and characterization of beta(2)-adrenergic (beta(2)AR) signaling genes. beta(2)AR function undergoes desensitization during persistent agonist exposure because of receptor phosphorylation by G-protein coupled receptor kinases (GRKs). GRK5 was found to be highly expressed in airway smooth muscle, the tissue target for beta-agonists. The coding region is polymorphic at codon 41, where Gin can be substituted by Leu (minor allele), but almost exclusively in those of African descent. In transfected cells, GRK5-Leu41 evoked a greater degree of agonist-promoted desensitization of adenylyl cyclase compared with GRK5-Gln4l. Consistent with this functional effect, agonist-promoted beta(2)AR phosphorylation was greater in cells expressing GRK5-Leu41, as was the rate of agonist-promoted receptor internalization. In studies with mutated beta(2)AR lacking PKA-phosphorylation sites, this phenotype was confirmed as being GRK-specific. So, GRK5-Leu41 represents a gain-of-function polymorphism that evokes enhanced loss-of-function Of PAR during persistent agonist exposure, and thus may contribute to beta-agonist variability in asthma treatment of African-Americans.
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