Targeted disruption of the mouse beta1-adrenergic receptor gene: developmental and cardiovascular effects.
At least three distinct beta-adrenergic receptor (beta-AR) subtypes exist in mammals. These receptors modulate a wide variety of processes, from development and behavior, to cardiac function, metabolism, and smooth muscle tone. To understand the roles that individual beta-AR subtypes play in these processes, we have used the technique of gene targeting to create homozygous beta 1-AR null mutants (beta 1-AR -/-) in mice. The majority of beta 1-AR -/- mice die prenatally, and the penetrance of lethality shows strain dependence. Beta l-AR -/- mice that do survive to adulthood appear normal, but lack the chronotropic and inotropic responses seen in wild-type mice when beta-AR agonists such as isoproterenol are administered. Moreover, this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice. These findings occur despite persistent cardiac beta 2-AR expression, demonstrating the importance of beta 1-ARs for proper mouse development and cardiac function, while highlighting functional differences between beta-AR subtypes.
Pubmed ID: 8693001 RIS Download
Adenylyl Cyclases | Adrenergic beta-Agonists | Adrenergic beta-Antagonists | Aging | Animals | Cell Membrane | Chimera | Crosses, Genetic | Death | Female | Gene Expression | Heart | Heart Rate | Heart Ventricles | Homozygote | Imidazoles | Isoproterenol | Kinetics | Lung | Male | Methoxyhydroxyphenylglycol | Mice | Mice, Inbred C57BL | Mice, Inbred DBA | Mice, Knockout | Myocardial Contraction | Myocardium | Norepinephrine | Receptors, Adrenergic, beta-1 | Restriction Mapping | Stem Cells