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. 2002 May 15;364(Pt 1):73–79. doi: 10.1042/bj3640073

A novel pathway for adrenergic stimulation of cAMP-response-element-binding protein (CREB) phosphorylation: mediation via alpha1-adrenoceptors and protein kinase C activation.

Håkan Thonberg 1, J Magnus Fredriksson 1, Jan Nedergaard 1, Barbara Cannon 1
PMCID: PMC1222547  PMID: 11988078

Abstract

Because of the central role of adrenergic mechanisms in the expression of crucial genes during brown adipocyte differentiation, we examined the activation (phosphorylation) of CREB (cAMP-response-element-binding protein) in mouse brown adipocytes in primary culture. We found that noradrenaline ('norepinephrine') stimulated CREB phosphorylation rapidly (maximum effect in < or =5 min with slow decay) and efficiently (EC(50), 6 nM). The increase in CREB phosphorylation coincided with increased expression of an artificial cAMP-response-element-containing reporter construct. CREB phosphorylation was partly inhibitable, both by the beta-adrenergic antagonist propranolol and by the alpha(1)-adrenergic antagonist prazosin. Adenylate cyclase hyperactivation (by forskolin) could stimulate CREB phosphorylation to the same extent as noradrenaline. The alpha(1)-adrenergic agonist cirazoline also increased CREB phosphorylation. An increase in intracellular [Ca(2+)] had, however, no effect, but protein kinase C activation by PMA was a potent stimulator. The cirazoline-stimulated (alpha(1)-adrenergic) CREB phosphorylation was inhibited by a desensitizing pretreatment with PMA, demonstrating that the alpha(1)-stimulation was mediated via protein kinase C activation; neither Src nor extracellular-signal-regulated kinases 1 and 2 activation was involved in the signalling process. We conclude that CREB phosphorylation in brown adipocytes is mediated not only through the classical beta-adrenergic/cAMP pathway but also through a novel alpha(1)-adrenergic/protein kinase C/CREB pathway, which has not been described previously in any tissue.

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Selected References

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