Targeted Disruption of the β2 Adrenergic Receptor Gene

Abstract

␤-Adrenergic receptors (␤-ARs) are members of the superfamily of G-protein-coupled receptors that mediate the effects of catecholamines in the sympathetic nervous system. Three distinct ␤-AR subtypes have been identified (␤1-AR, ␤2-AR, and ␤3-AR). In order to define further the role of the different ␤-AR subtypes, we have used gene targeting to inactivate selectively the ␤2-AR gene in mice. Based on intercrosses of heterozygous knockout (␤2-AR ؉/؊) mice, there is no prenatal lethality associated with this mutation. Adult knockout mice (␤2-AR ؊/؊) appear grossly normal and are fertile. Their resting heart rate and blood pressure are normal, and they have a normal chronotropic response to the ␤-AR agonist isoproterenol. The hypotensive response to isoproterenol, however, is significantly blunted compared with wild type mice. Despite this defect in vasodilation, ␤2-AR ؊/؊ mice can still exercise normally and actually have a greater total exercise capacity than wild type mice. At comparable workloads, ␤2-AR ؊/؊ mice had a lower respiratory exchange ratio than wild type mice suggesting a difference in energy metabolism. ␤2-AR ؊/؊ mice become hypertensive during exercise and exhibit a greater hypertensive response to epinephrine compared with wild type mice. In summary, the primary physiologic consequences of the ␤2-AR gene disruption are observed only during the stress of exercise and are the result of alterations in both vascular tone and energy metabolism.

β 2 -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

“…Our previous studies were performed by using BALB/c and C57BL/6J mice (14), whereas the ␤ 2 -AR Ϫ/Ϫ mouse was constructed in the wild-type FVB/N background (21). Minimal intracellular mucin was observed in saline-challenged FVB/N mice assessed by using periodic acid f luorescent Schiff (PAFS) staining, whereas in antigenchallenged FVB/N mice there was abundant intracellular mucin (Fig.…”

Stimulation of the B Cell Receptor, CD86 (B7-2), and the β2-Adrenergic Receptor Intrinsically Modulates the Level of IgG1 and IgE Produced per B Cell

“…Female BALB/c mice (H-2 d -restricted) were obtained from Harlan Sprague-Dawley (Indianapolis, IN), male and female ␤ 2 ARdeficient mice (H-2 q -restricted) (26) were generously provided by Dr. Brian Kobilka (Stanford University, Stanford, CA), and CD86-deficient mice (H-2 d -restricted) (27) were generously provided by Dr. Arlene Sharpe (Brigham and Women's Hospital, Boston, MA). The ␤ 2 AR-deficient mouse was generated by homologous recombination resulting in the insertion of a neomycin resistance gene cassette into the fourth transmembrane domain of the ␤ 2 AR gene and has been described previously (26). The CD86-deficient mouse was generated by homologous recombination resulting in the replacement of a portion of the IgV region of the CD86 gene with a neomycin resistance gene cassette and has been described previously (27).…”

Xamoterol impairs hippocampus-dependent emotional memory retrieval via Gi/o-coupled β2-adrenergic signaling

“…Wild-type, b 1 KO, and b 2 KO mice were on a hybrid 129/Sv x C57BL/6 background and were derived by mating either heterozygotes or homozygotes (Rohrer et al 1996;Chruscinski et al 1999). Gender and parental genotype did not affect the results, so data were combined.…”