title: beta1-adrenergic receptors mediate beta3-adrenergic-independent effects of CGP 12177 in brown adipose tissue.
abstract: CGP 12177 is a beta-adrenergic receptor (AR) ligand that has been used to characterize the beta3-AR and the putative beta4-AR. The ability of CGP 12177 to activate beta1-AR when overexpressed in vitro and the presence of beta1-AR in tissues expressing putative beta4-AR prompted us to investigate the actions of CGP 12177 at recombinant and natively-expressed beta-AR. CGP 12177 potently activated recombinant rat and human beta1-AR expressed in Chinese hamster ovary cells. This activation, like that of putative beta4-AR, was resistant to blockade by selective and nonselective beta-AR antagonists. Brown fat has been proposed to contain beta4-AR, as evidenced by the presence of CGP 12177-mediated thermogenesis in mice lacking beta3-AR. Therefore, the identity of the receptors mediating CGP 12177 responses in brown fat was examined using wild-type mice and mice lacking beta1-AR or beta3-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 beta1-AR. Moreover, the high-affinity site was absent in mice lacking beta1-AR. In contrast, the low-affinity, CGP 20712-resistant activation by CGP 12177 was absent in mice lacking beta3-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 beta-AR (i.e., beta4-AR) are mediated via an atypical interaction with beta1-AR.
authors.affiliation: Cellular and Clinical Neurobiology Program, Department of Psychiatry, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Konkar
authors.forename: Y
authors.initials: Y
authors.lastname: Zhai
authors.forename: J G
authors.initials: JG
authors.lastname: Granneman
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism*; D022702:Receptors, Adrenergic, beta-3; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D022702:Receptors, Adrenergic, beta-3; D011994:Recombinant Proteins; D000262:Adenylyl Cyclases; C033394:CGP 12177