Functional responses of human β1 adrenoceptors with defined haplotypes for the common 389R>G and 49S>G polymorphisms

Objectives The human beta1-adrenoceptor (beta1-AR) is an important therapeutic target for cardiovascular diseases and has two common functional polymorphisms (49S>G and 389R>G). These polymorphisms have only been studied in isolation, however, and not in the context of the four haplotypes (SR, SG, GR and GG) that exist in native beta1-ARs. Results The affinity for the P-adrenoceptor ligand, [1251]cyanopindolol, was not significantly different across the haplotypes, but a high affinity state for the beta1-AR could only be demonstrated for receptors carrying the 389R substitution. Both basal (GR 36.3 +/- 2.9* vs. SR 16.5 +/- 3.6 and GG 31.7 +/- 1.4* vs. SG 15.6 +/- 1.5 pmol/mg protein; *P < 0.001) and maximal (GR 163 +/- 7.6 vs. SR 124 +/- 8.1* and GG 75.0 +/- 1.0 vs. SG 52.4 +/- 1.1* pmol/mg protein; *P < 0.001) isoprenaline-evoked cAMP production was significantly affected by both substitutions. Incubation with isoprenaline (10 muM for 30 min or 20 h) caused increased down-regulation of beta1-ARs in cells expressing GG and GRMethods To address this, the function of each of the receptor haplotypes was studied in HEK 293 cells stably transfected with appropriately modified human beta1-adrenoceptor cDNA sequence. haplotypes (at 20 h percentage fall respectively -28.1 +/- 5.2 and -38.2 +/- 3.0). Conclusions These data highlight important functional differences between the common beta1-AR haplotypes and the need for consideration of haplotypes and not individual genotypes in determining the in-vivo role of these polymorphisms within this important drug target. Pharmacogenetics 14:343-349 (C) 2004 Lippincott Williams Wilkins.