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Vol. 57, Issue 2, 252-258, February 2000
1-Adrenergic Receptors Mediate 3-Adrenergic-Independent
Effects of CGP 12177 in Brown Adipose Tissue
Cellular and Clinical Neurobiology Program, Department of
Psychiatry and Behavioral Neurosciences, Wayne State University School
of Medicine, Detroit, Michigan.
CGP 12177 is a 
-adrenergic receptor (AR) ligand that has been used
to characterize the 3-AR and the putative 4-AR. The ability of
CGP 12177 to activate 1-AR when overexpressed in vitro and the
presence of 1-AR in tissues expressing putative 4-AR prompted us
to investigate the actions of CGP 12177 at recombinant and
natively-expressed -AR. CGP 12177 potently activated recombinant rat
and human 1-AR expressed in Chinese hamster ovary cells. This
activation, like that of putative 4-AR, was resistant to blockade by
selective and nonselective -AR antagonists. Brown fat has been
proposed to contain 4-AR, as evidenced by the presence of CGP
12177-mediated thermogenesis in mice lacking 3-AR. Therefore, the
identity of the receptors mediating CGP 12177 responses in brown fat
was examined using wild-type mice and mice lacking 1-AR or 3-AR.
In wild-type mice, CGP 12177 activated adenylyl cyclase via high- and
low-affinity sites. The high-affinity site, but not the low-affinity
site, was blocked by CGP 20712 with potency indicating an interaction
with 1-AR. Moreover, the high-affinity site was absent in mice
lacking 1-AR. In contrast, the low-affinity, CGP 20712-resistant
activation by CGP 12177 was absent in mice lacking 3-AR. Rather,
activation occurred exclusively through the high-affinity, CGP
20712-sensitive site. These data indicate that the actions of CGP 12177 in brown fat that have been attributed to novel -AR (i.e., 4-AR)
are mediated via an atypical interaction with 1-AR.
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