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J Biol Chem, Vol. 274, Issue 17, 12017-12022, April 23, 1999

The ₃-Adrenergic Receptor Activates Mitogen-activated Protein Kinase in Adipocytes through a G_i-dependent Mechanism

Kurt J. Soeder, Sheridan K. Snedden, Wenhong Cao^§, Gregory J. Della Rocca^¶, Kiefer W. Daniel^§, Louis M. Luttrell, and Sheila Collins^§

From the Departments of ^§ Psychiatry and Behavioral Sciences,  Pharmacology, ^¶ Biochemistry, and  Medicine, Duke University Medical Center, Durham, North Carolina 27710

Promiscuous coupling between G protein-coupled receptors and multiple species of heterotrimeric G proteins provides a potential mechanism for expanding the diversity of G protein-coupled receptor signaling. We have examined the mechanism and functional consequences of dual G_s/G_i protein coupling of the ₃-adrenergic receptor (₃AR) in 3T3-F442A adipocytes. The ₃AR selective agonist disodium (R,R)-5-[2[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL316,243) stimulated a dose-dependent increase in cAMP production in adipocyte plasma membrane preparations, and pretreatment of cells with pertussis toxin resulted in a further 2-fold increase in cAMP production by CL316,243. CL316,243 (5 µM) stimulated the incorporation of 8-azido-[³²P]GTP into G_s (1.57 ± 0.12; n = 3) and G_i (1.68 ± 0.13; n = 4) in adipocyte plasma membranes, directly demonstrating that ₃AR stimulation results in G_i-GTP exchange. The ₃AR-stimulated increase in 8-azido-[³²P]GTP labeling of G_i was equivalent to that obtained with the A₁-adenosine receptor agonist N⁶-cyclopentyladenosine (1.56 ± 0.07; n = 4), whereas inclusion of unlabeled GTP (100 µM) eliminated all binding. Stimulation of the ₃AR in 3T3-F442A adipocytes led to a 2-3-fold activation of mitogen-activated protein (MAP) kinase, as measured by extracellular signal-regulated kinase-1 and -2 (ERK1/2) phosphorylation. Pretreatment of cells with pertussis toxin (PTX) eliminated MAP kinase activation by ₃AR, demonstrating that this response required receptor coupling to G_i. Expression of the human ₃AR in HEK-293 cells reconstituted the PTX-sensitive stimulation of MAP kinase, demonstrating that this phenomenon is not exclusive to adipocytes or to the rodent ₃AR. ERK1/2 activation by the ₃AR was insensitive to the cAMP-dependent protein kinase inhibitor H-89 but was abolished by genistein and AG1478. These data indicate that constitutive ₃AR coupling to G_i proteins serves both to restrain G_s-mediated activation of adenylyl cyclase and to initiate additional signal transduction pathways, including the ERK1/2 MAP kinase cascade.

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