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.
Rohrer
D K
DK
Department of Pediatrics, Stanford University, CA 94305, USA.
Desai
K H
KH
Jasper
J R
JR
Stevens
M E
ME
Regula
D P
DP
Barsh
G S
GS
Bernstein
D
D
Kobilka
B K
BK
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000375:Aging; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D002678:Chimera; D003433:Crosses, Genetic; D003643:Death; D005260:Female; D015870:Gene Expression; D006321:Heart / Q000254:growth & development / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles; D006720:Homozygote; D007093:Imidazoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008168:Lung / Q000502:physiology; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015183:Restriction Mapping; D013234:Stem Cells
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D007093:Imidazoles; D018342:Receptors, Adrenergic, beta-1; D008734:Methoxyhydroxyphenylglycol; C049763:CGP 20712A; D000262:Adenylyl Cyclases; D007545:Isoproterenol; C010117:3,4-dihydroxyphenylglycol; D009638:Norepinephrine