PMID: 11336791May 5, 2001Paper

Analysis of inhibition by H89 of UCP1 gene expression and thermogenesis indicates protein kinase A mediation of beta(3)-adrenergic signalling rather than beta(3)-adrenoceptor antagonism by H89

Biochimica Et Biophysica Acta
J M FredrikssonJ Nedergaard

Abstract

Although it has generally been assumed that protein kinase A (PKA) is essential for brown adipose tissue function, this has not as yet been clearly demonstrated. H89, an inhibitor of PKA, was used here to inhibit PKA activity. In cell extracts, it was confirmed that norepinephrine stimulated PKA activity, which was abolished by H89 treatment. In isolated brown adipocytes, H89 inhibited adrenergically induced thermogenesis (with an IC(50) of approx. 40 microM), and in cultured cells, adrenergically stimulated expression of the uncoupling protein-1 (UCP1) gene was abolished by H89 (full inhibition with 50 microM). However, H89 has been reported to be an adrenergic antagonist on beta(1)/beta(2)-adrenoceptors (AR). Although adrenergic stimulation of thermogenesis and UCP1 gene expression are mediated via beta(3)-ARs, it was deemed necessary to investigate whether H89 also had antagonistic potency on beta(3)-ARs. It was found that EC(50) values for beta(3)-AR-selective stimulation of cAMP production (with BRL-37344) in brown adipose tissue membrane fractions and in intact cells were not affected by H89. Similarly, the EC(50) of adrenergically stimulated oxygen consumption was not affected by H89. As H89 also abolished forskolin-indu...Continue Reading

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Citations

Mar 4, 2015·Stem Cells International·Magali KouidhiChristian Dani
Jan 14, 2012·Journal of Molecular Cell Biology·Shuangtao MaZhiming Zhu
Jun 5, 2014·Biophysical Journal·Masaaki K SatoYuichi Inoue
Apr 10, 2004·The Journal of Biological Chemistry·Jong S RimLeslie P Kozak
Jul 30, 2020·Critical Reviews in Food Science and Nutrition·L Melguizo RodríguezO García-Martínez
Apr 22, 2016·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Lorna M DicksonBarton Wicksteed
Nov 26, 2003·European Journal of Cancer Prevention : the Official Journal of the European Cancer Prevention Organisation (ECP)·S Böckmann, B Nebe
Oct 17, 2002·American Journal of Physiology. Gastrointestinal and Liver Physiology·Irina ShabalinaJan Nedergaard
Jan 13, 2004·Physiological Reviews·Barbara Cannon, Jan Nedergaard
Oct 1, 2014·Temperature : Multidisciplinary Biomedical Journal·Christine K DaoEdward M Mills
Jan 10, 2002·Cellular Signalling·Gunnar Schulte, Bertil B Fredholm
Sep 25, 2021·Nature Immunology·Jingfei YaoYifu Qiu

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