Targeted disruption of the mouse beta1-adrenergic receptor gene: developmental and cardiovascular effects.

TLDR

Beta‑adrenergic receptors comprise at least three subtypes in mammals and regulate diverse processes including development, behavior, cardiac function, metabolism, and smooth‑muscle tone. The study aimed to elucidate the specific roles of beta‑1 adrenergic receptors by generating homozygous beta‑1‑AR knockout mice via gene targeting. Gene targeting was used to produce homozygous beta‑1‑AR null mutant mice. Beta‑1‑AR knockout mice show strain‑dependent prenatal lethality, and survivors lack heart‑rate and contractility responses to beta‑adrenergic agonists with markedly reduced cardiac adenylate‑cyclase activation, highlighting beta‑1‑AR’s essential role in development and cardiac function despite persistent beta‑2‑AR expression.

Abstract

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.