Multiple beta adrenergic receptor subclasses mediate the l-isoproterenol-induced lipolytic response in rat adipocytes.
l-Isoproterenol has been proposed to stimulate lipolysis in rat epididymal adipocytes via atypical beta adrenergic receptors, whereas radioligand binding studies only revealed the presence of beta 1 adrenergic receptors on adipocyte membranes. We have made use of the unique properties of CGP12177 to evidence that both the beta 1 and the atypical beta adrenergic receptor subtypes are mediating the lipolytic response of rat epididymal adipocytes to l-isoproterenol. CGP12177, an antagonist with high affinity for beta 1 receptors, triggers lipolysis by specifically stimulating the atypical receptors. For this response, CGP12177 displays low potency (EC50 = 68 nM), but high intrinsic activity (94% relative to l-isoproterenol). At low concentrations (3 nM), CGP12177 inhibits the lipolytic response to 10 nM l-isoproterenol by 43%, indicating that at least this fraction of the response is beta 1 receptor-mediated. The response to BRL37344, which is a selective agonist for the atypical receptors, is not inhibited by CGP12177. The pA2 values of the beta adrenergic antagonists propranolol, metoprolol and atenolol were calculated from the rightward shifts that they impose on dose-response curves of both l-isoproterenol and CGP12177. With l-isoproterenol, these values (6.54, 5.83 and 5.07, respectively) are lower than those expected for beta 1 and beta 2 receptors, indicating that atypical receptors are also involved in the lipolytic response to this agonist. With CGP12177, the pA2 values of propranolol, metoprolol and atenolol are even lower (5.80, 5.03 and 4.06, respectively), and are likely to be a more accurate reflection of their affinities for the atypical receptors.
Van Liefde
I
I
Department of Protein Chemistry, Free University of Brussels (V.U.B.) Belgium.
Van Witzenburg
A
A
Vauquelin
G
G
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000502:physiology*
D004983:Ethanolamines; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; C057368:BRL 37344; D011433:Propranolol; D007545:Isoproterenol; C033394:CGP 12177