FVB.129-Adrb2^tm1Bkk/J

Stock number: 031496
Product name: β 2-AR^-
Strain synonyms: β 2 AR-KO
Research areas: Cardiovascular Research, Metabolism Research, Neurobiology Research

Description

Homozygous Adrb2 knock-out mice on the FVB/N background exhibit decreased body weight, increased exercise capacity, exercise-induced hypertension, TAC-induced cardiac hypertrophy and a fatal response to high dose doxorubicin. This strain may be useful for studying energy metabolism and cardiomyopathy, and, in particular, a cardioprotective role for β 2-AR.

Detailed description

Adrb2 (adrenergic receptor, beta 2) encodes a member of the family of G protein-coupled receptors. The three subtypes of adrenergic receptor (β 1, β 2, and β 3) are expressed in the heart and play a role in the activation of adenylyl cyclase and subsequent regulation of cardiac function and remodeling. β 2-AR knock-out (KO) mice contain a neomycin cassette that disrupts the end of the fourth transmembrane segment rendering the β 2-AR receptor nonfunctional. Homozygous mice are viable and fertile, but exhibit decreased body and epidydmal fat pad weight. During exercise, β 2-AR null mice exhibit a greater total exercise capacity and a lower respiratory exchange ratio. Hypertension is observed during exercise and following treatment with epinephrine. Administration of the β-AR agonist isoproterenol to homozygous mice results in a blunted hypotensive response, although the chronotropic response is normal.

Administration of a single high dose of doxorubicin to β 2-AR KO mice results in death within 30 minutes preceded by decreased contractile function, hypotension and QTc prolongation. Doxorubicin produces no acute cardiotoxicity in the β 1-AR KO and has no effect on the double KO. Following TAC (transverse aortic constriction) β 2-AR KO mice exhibit substantial hypertrophy; a 21% increase in heart to body weight ratio (similar to wild-type) is observed in the β 1-AR knockout. In the double KO, no hypertrophy or increase in weight ratio is observed.

This strain may be useful for studying energy metabolism and cardiomyopathy, and, in particular, a cardioprotective role for β 2-AR.

The Adrb1^tm1Bkk is distributed on the FVB/N background as Stock No. 031490. A double Adrb1/Adrb2 knock-out is distributed as Stock No. 003810 on a mixed background.

Development

A targeting vector containing a neomycin resistance gene driven by the mouse phosphoglycerate kinase promoter was used to disrupt the end of the fourth transmembrane segment - rendering the receptor nonfunctional. The construct was transfected into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric males were mated to FVB/N females. The colony then was crossed to FVB/N mice for at least ten generations. Upon arrival, mice were bred to FVB/NJ (Stock No. 001800) for at least one generation to establish the colony.

Allele

Symbol: Adrb2^tm1Bkk
Name: targeted mutation 1, Brian K Kobilka
MGI accession ID: MGI:1859675
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: Adrb2^-; Beta2-AR; beta2AR^-; Beta2-KO
Marker symbol: Adrb2
Marker name: adrenergic receptor, beta 2
Marker synonyms: Adrb-2; ADRB2R; ADRBR; ARB2; B2AR; Badm; BAR; beta 2-adrenoceptor; beta 2-AR; BETA2AR; Gpcr7
Chromosome: 18
Strain of origin: (129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Molecular note: A neomycin selection cassette was inserted into the sequence encoding the fourth transmembrane segment. This mutation is predicted to eliminate expression of a functional receptor. Ligand binding experiments confirmed that no functional receptor was expressed in the lung of homozygous mice.