B6.129-Adra2a^tm1Bkk/J

Stock number: 004367
Product name: α_2A-AR KO
Research areas: Cardiovascular Research, Neurobiology Research

Description

These Adra2a knock-out mice exhibit a resting tachycardia significantly greater than normal and a reduced expression of the adrenergic receptor in the brain.

Detailed description

Mice that are homozygous for the targeted mutation are viable, normal in size and do not display any gross physical or behavioral abnormalities. Expression of the receptor in the brain was significantly reduced as assessed by antagonist binding, which indicated a 90% reduction. The antagonist binding assay is not entirely specific for the receptor, as the residual 10% binding was attributable to a different subtype of receptor. Mutant mice exhibit a resting tachycardia of more than 180 beats/min greater than normal. Although mutant mice do not have elevated blood pressure, administration of the hypotensive agonist, dexmedetomidine, does not reduce blood pressure. Electrical stimulation of isolated heart atria at frequencies mimicking physiological sympathetic nerve activity results in increased release of noradrenaline at high frequencies and inhibited release at low frequencies. Noradrenaline release from isolated wildtype atria is higher at high frequencies than at low frequencies. Inhibition of neurogenic contraction response to electrical stimulation in isolated vas deferens by dexmedetomidine is reduced in the mutant.

Development

A targeting vector containing neomycin resistance gene driven by the mouse phosphoglycerate kinase promoter and herpes simplex virus thymidine kinase gene was used to disrupt the sequence of the targeted gene encoding the third transmembrane domain. The construct was electroporated into 129X1/SvJ x 129S1/Sv derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were aggregated with 8-cell FVB/N morulae. The resulting chimeric animals were backcrossed to C57BL/6 mice.

Allele

Symbol: Adra2a^tm1Bkk
Name: targeted mutation 1, Brian K Kobilka
MGI accession ID: MGI:2179108
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Adra2a
Marker name: adrenergic receptor, alpha 2a
Chromosome: 19
Strain of origin: (129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Molecular note: A neomycin cassette inserted into the gene by homologous recombination resulted in a premature stop codon within the third transmembrane domain. Confirmation of the targeting event was demonstrated through Southern analysis.