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J Biol Chem, Vol. 274, Issue 24, 16694-16700, June 11, 1999
2 Adrenergic Receptor Gene
,
,,, and**
From the Department of Molecular and
Cellular Physiology, ** Division of Cardiovascular Medicine,
Department of Pediatrics, the Howard
Hughes Medical Institute, Stanford University,
Stanford, California 94305 and the ¶ Department of Molecular
Pharmacology, Roche Bioscience, Palo Alto, California 94304
-Adrenergic receptors (-ARs) are members of
the superfamily of G-protein-coupled receptors that mediate the effects
of catecholamines in the sympathetic nervous system. Three distinct
-AR subtypes have been identified (1-AR, 2-AR, and 3-AR).
In order to define further the role of the different -AR subtypes,
we have used gene targeting to inactivate selectively the 2-AR gene
in mice. Based on intercrosses of heterozygous knockout (2-AR +/
)
mice, there is no prenatal lethality associated with this mutation. Adult knockout mice (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 -AR agonist isoproterenol. The hypotensive response to isoproterenol, however, is
significantly blunted compared with wild type mice. Despite this defect
in vasodilation, 2-AR / mice can still exercise normally and
actually have a greater total exercise capacity than wild type mice. At
comparable workloads, 2-AR / mice had a lower respiratory
exchange ratio than wild type mice suggesting a difference in energy
metabolism. 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
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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