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Vol. 60, Issue 3, 577-583, September 2001
-Adrenergic Receptor Subtype-Specific Signaling in Cardiac
Myocytes from 1 and 2 Adrenoceptor
Knockout Mice
Howard Hughes Medical Institute, Stanford University Medical
School, Stanford, California
The sympathetic nervous system modulates cardiac contractility and rate
by activating 
-adrenergic receptors (AR) expressed on cardiac
myocytes and specialized cells in the sinoatrial node and the
conduction system. Recent clinical studies have suggested that
-adrenergic receptors also play a role in cardiac remodeling that
occurs in the pathogenesis of cardiomyopathy. Both 1 and 2 adrenergic receptors are expressed in human and murine
hearts. We have examined the effect of AR activation on the
spontaneous contraction rate of neonatal myocyte cultures from
wild-type and receptor knockout (KO) mice (1AR-KO,
2AR-KO and 12AR-KO mice).
Stimulation of the 1AR in 2AR-KO myocytes
produces the greatest increase in contraction rate through a signaling
pathway that requires protein kinase A (PKA) activation. In contrast, stimulation of the 2AR in 1AR-KO myocytes
results in a biphasic effect on contraction rate with an initial
increase in rate that does not require PKA, followed by a decrease in
rate that involves coupling to a pertussis toxin sensitive G protein. A
small isoproterenol-induced decrease in contraction rate observed in
12AR-KO myocytes can be attributed to the
3AR. These studies show that all three AR subtypes
are expressed in neonatal cardiac myocytes, and the 1AR and 2AR couple to distinct signaling pathways.
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