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J Biol Chem, Vol. 274, Issue 53, 37770-37780, December 31, 1999

A Dual Component Analysis Explains the Distinctive Kinetics of cAMP Accumulation in Brown Adipocytes^*

Gennady E. Bronnikov, Shi-Jin Zhang, Barbara Cannon, and Jan Nedergaard^§

From the Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, S-106 91 Stockholm, Sweden

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 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 ₁-component of the norepinephrine response revealed the underlying existence of a much larger stimulatory ₃-component which displayed monophasic Michaelis-Menten kinetics. The inhibitory ₁-component (which was also monophasic but had a 2-fold higher EC₅₀) was mediated via an increase in [Ca²⁺]_i; the protein kinase C pathway was not involved. The [Ca²⁺]_i increase which resulted in massive inhibition of cAMP accumulation was very low: <100 nM. The [Ca²⁺]_i signal stimulated a calmodulin-controlled phosphodiesterase, possibly PDE-1. The acquirement of this specific interaction pattern between - and ₁-adrenergic stimulation was thus part of the differentiation program of the brown adipocytes. It was concluded that an array of synergistic or inhibitory ₁/ 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.

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^* This work was supported by a grant from the Swedish Natural Science Research Council (to B. C. and J. N.) and Russian Foundation for Basic Research Grant 98-04-49214 (to G. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

On leave from the Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Russia. Present address: Centre for Molecular Biology and Medicine, Epworth Hospital, 89 Bridge Rd., Richmond (Melbourne), 3121 Australia.

^§ To whom correspondence should be addressed: The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, S-106 91 Stockholm, Sweden. Tel.: 46-8-164128; Fax: 46-8-156756; E-mail: jan@metabol.su.se.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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