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J. Biol. Chem., Vol. 275, Issue 30, 22670-22677, July 28, 2000
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From The Wenner-Gren Institute, The Arrhenius Laboratories F3,
Stockholm University, SE-106 91 Stockholm, Sweden
A novel signaling pathway for mediation of
3- and 
1-Adrenergic Erk1/2
Activation Is Src- but Not Gi-mediated in Brown
Adipocytes*
,
3-adrenergic activation of the mitogen-activated
protein kinases Erk1/2 (associated with proliferation, differentiation,
and apoptosis) has recently been proposed, which implies mediation via
constitutively coupled Gi-proteins and G
-subunits,
distinct from the classical cAMP pathway of -adrenergic stimulation.
To verify the significance of this pathway in cells in primary cultures
that entopically express 3-adrenoreceptors, we examined
the functionality of this pathway in cultured brown adipocytes.
Norepinephrine activated Erk1/2 via both 3 receptors and
1 receptors but not via 2 receptors. Forskolin induced Erk1/2 activation similarly to 3
activation, indicating cAMP-mediation; this induction could be
inhibited with H89, implying protein kinase A mediation. The
Gi-pathway was functional in these cells, as pertussis
toxin increased agonist-induced cAMP accumulation. However, pertussis
toxin was unable to affect adrenergically induced Erk1/2 activation.
Also, wortmannin was without effect, implying that G activation
of the phosphatidylinositol 3-kinase pathway was not involved. PP1/2,
which inhibits Src, abolished both 3- and
1-induced Erk1/2 activation. Thus, the proposed novel
Gi pathway for 3 mediation is not universal,
because it is not functional in the untransformed primary cell culture
system with entopically expressed 3 receptors examined
here. Here, the 3 signal is mediated classically via
cAMP/protein kinase A. 3 and 1 signals
converge at Src, which thus mediates Erk1/2 activation in both pathways.
*
This work was supported by the Swedish Cancer Foundation,
the Swedish Natural Science Research Council, and Helge Ax:son Johnsons stiftelse.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.
To whom correspondence should be addressed. Tel.: 46-8-164125;
Fax: 46-8-156756; E-mail: johanna@zoofys.su.se.
§
Present address: Karo Bio AB, Novum, SE-141 57 Huddinge, Sweden.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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