beta 1-adrenergic receptors mediate beta 3-adrenergic-independent effects of CGP 12177 in brown adipose tissue

CGP 12177 is a beta-adrenergic receptor (AR) ligand that has been used to c haracterize the beta 3-AR and the putative beta 4-AR. The ability of CGP 12 177 to activate beta 1-AR when overexpressed in vitro and the presence of b eta 1-AR in tissues expressing putative beta 4-AR prompted us to investigat e the actions of CGP 12177 at recombinant and natively-expressed beta-AR. C GP 12177 potently activated recombinant rat and human beta 1-AR expressed i n Chinese hamster ovary cells. This activation, like that of putative beta 4-AR, was resistant to blockade by selective and nonselective beta-AR antag onists. Brown fat has been proposed to contain beta 4-AR, as evidenced by t he presence of CGP 12177-mediated thermogenesis in mice lacking beta 3-AR. Therefore, the identity of the receptors mediating CGP 12177 responses in b rown fat was examined using wild-type mice and mice lacking beta 1-AR or be ta 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 si te, was blocked by CGP 20712 with potency indicating an interaction with be ta 1-AR. Moreover, the high-affinity site was absent in mice lacking beta 1 -AR. In contrast, the low-affinity, CGP 20712-resistant activation by CGP 1 2177 was absent in mice lacking beta 3-AR. Rather, activation occurred excl usively through the high- affinity, CGP 20712-sensitive site. These data in dicate that the actions of CGP 12177 in brown fat that have been attributed to novel beta-AR (i.e., beta 4-AR) are mediated via an atypical interactio n with beta 1-AR.