title: A dual component analysis explains the distinctive kinetics of cAMP accumulation in brown adipocytes.
abstract: The mechanism behind the distinctive non-Michaelis-Menten, bell-shaped kinetics of cAMP accumulation in brown adipocytes (which underlies the similar kinetics of UCP1 and beta(1)-adrenoreceptor gene expression) was investigated. A theoretical dual component analysis indicated that the observed dose-response curves could be constructed as the resultant of a stimulatory and an inhibitory component. Experimentally, inhibition of the alpha(1)-component of the norepinephrine response revealed the underlying existence of a much larger stimulatory beta(3)-component which displayed monophasic Michaelis-Menten kinetics. The inhibitory alpha(1)-component (which was also monophasic but had a 2-fold higher EC(50)) was mediated via an increase in [Ca(2+)](i); the protein kinase C pathway was not involved. The [Ca(2+)](i) increase which resulted in massive inhibition of cAMP accumulation was very low: <100 nM. The [Ca(2+)](i) signal stimulated a calmodulin-controlled phosphodiesterase, possibly PDE-1. The acquirement of this specific interaction pattern between beta- and alpha(1)-adrenergic stimulation was thus part of the differentiation program of the brown adipocytes. It was concluded that an array of synergistic or inhibitory alpha(1)/beta interactions occur in the adrenergic regulation of this cell type which is unique in its dependence upon adrenergic stimulation for cellular proliferation, differentiation, and metabolic function.
authors.affiliation: Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, S-106 91 Stockholm, Sweden.
authors.forename: G E
authors.initials: GE
authors.lastname: Bronnikov
authors.forename: S J
authors.initials: SJ
authors.lastname: Zhang
authors.forename: B
authors.initials: B
authors.lastname: Cannon
authors.forename: J
authors.initials: J
authors.lastname: Nedergaard
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D009638:Norepinephrine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D022702:Receptors, Adrenergic, beta-3
chemical_list: D000318:Adrenergic beta-Agonists; D002147:Calmodulin; D010726:Phosphodiesterase Inhibitors; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; D000242:Cyclic AMP; D011493:Protein Kinase C; D010727:Phosphoric Diester Hydrolases; D007545:Isoproterenol; D002118:Calcium; D009638:Norepinephrine