Targeted disruption of the β2 adrenergic receptor gene

被引:251
作者
Chruscinski, AJ
Rohrer, DK
Schauble, E
Desai, KH
Bernstein, D
Kobilka, BK [1 ]
机构
[1] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA
[2] Stanford Univ, Dept Cellular & Mol Physiol, Stanford, CA 94305 USA
[3] Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA
[4] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA
[5] Roche Biosci, Dept Mol Pharmacol, Palo Alto, CA 94304 USA
关键词
D O I
10.1074/jbc.274.24.16694
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
beta-Adrenergic receptors (beta-ARs) are members of the superfamily of G-protein-coupled receptors that mediate the effects of catecholamines in the sympathetic nervous system. Three distinct beta-AR subtypes have been identified (beta 1-AR, beta 2-AR, and beta 3-AR), In order to define further the role of the different P-AR subtypes, we have used gene targeting to inactivate selectively the beta 2-AR gene in mice. Based on intercrosses of heterozygous knockout (beta 2-AR +/-) mice, there is no prenatal lethality associated with this mutation. Adult knockout mice (beta 2-AR -/-) appear grossly normal and are fertile. Their resting heart rate and blood pressure are normal, and they have a normal chronotropic response to the beta-AR agonist isoproterenol, The hypotensive response to isoproterenol, however, is significantly blunted compared with wild type mice. Despite this defect in vasodilation, beta 2-AR -/- mice can still exercise normally and actually have a greater total exercise capacity than wild type mice. At comparable workloads, beta 2-AR -/- mice had a lower respiratory exchange ratio than wild type mice suggesting a difference in energy metabolism. beta 2-AR -/- mice become hypertensive during exercise and exhibit a greater hypertensive response to epinephrine compared with wild type mice. In summary, the primary physiologic consequences of the beta 2-AR gene disruption are observed only during the stress of exercise and are the result of alterations in both vascular tone and energy metabolism.
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收藏
页码:16694 / 16700
页数:7
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