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The beta3-adrenergic receptor activates mitogen-activated protein kinase in adipocytes through a Gi-dependent mechanism.

Publication ,  Journal Article
Soeder, KJ; Snedden, SK; Cao, W; Della Rocca, GJ; Daniel, KW; Luttrell, LM; Collins, S
Published in: J Biol Chem
April 23, 1999

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 Gs/Gi protein coupling of the beta3-adrenergic receptor (beta3AR) in 3T3-F442A adipocytes. The beta3AR 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 microM) stimulated the incorporation of 8-azido-[32P]GTP into Galphas (1.57 +/- 0.12; n = 3) and Galphai (1. 68 +/- 0.13; n = 4) in adipocyte plasma membranes, directly demonstrating that beta3AR stimulation results in Gi-GTP exchange. The beta3AR-stimulated increase in 8-azido-[32P]GTP labeling of Galphai 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 microM) eliminated all binding. Stimulation of the beta3AR 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 beta3AR, demonstrating that this response required receptor coupling to Gi. Expression of the human beta3AR 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 beta3AR. ERK1/2 activation by the beta3AR was insensitive to the cAMP-dependent protein kinase inhibitor H-89 but was abolished by genistein and AG1478. These data indicate that constitutive beta3AR coupling to Gi proteins serves both to restrain Gs-mediated activation of adenylyl cyclase and to initiate additional signal transduction pathways, including the ERK1/2 MAP kinase cascade.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

April 23, 1999

Volume

274

Issue

17

Start / End Page

12017 / 12022

Location

United States

Related Subject Headings

  • Receptors, Adrenergic, beta-3
  • Receptors, Adrenergic, beta
  • Protein Binding
  • Mice
  • Lipolysis
  • Humans
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Enzyme Activation
  • Dioxoles
  • Calcium-Calmodulin-Dependent Protein Kinases
 

Citation

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Soeder, K. J., Snedden, S. K., Cao, W., Della Rocca, G. J., Daniel, K. W., Luttrell, L. M., & Collins, S. (1999). The beta3-adrenergic receptor activates mitogen-activated protein kinase in adipocytes through a Gi-dependent mechanism. J Biol Chem, 274(17), 12017–12022. https://doi.org/10.1074/jbc.274.17.12017
Soeder, K. J., S. K. Snedden, W. Cao, G. J. Della Rocca, K. W. Daniel, L. M. Luttrell, and S. Collins. “The beta3-adrenergic receptor activates mitogen-activated protein kinase in adipocytes through a Gi-dependent mechanism.J Biol Chem 274, no. 17 (April 23, 1999): 12017–22. https://doi.org/10.1074/jbc.274.17.12017.
Soeder KJ, Snedden SK, Cao W, Della Rocca GJ, Daniel KW, Luttrell LM, et al. The beta3-adrenergic receptor activates mitogen-activated protein kinase in adipocytes through a Gi-dependent mechanism. J Biol Chem. 1999 Apr 23;274(17):12017–22.
Soeder, K. J., et al. “The beta3-adrenergic receptor activates mitogen-activated protein kinase in adipocytes through a Gi-dependent mechanism.J Biol Chem, vol. 274, no. 17, Apr. 1999, pp. 12017–22. Pubmed, doi:10.1074/jbc.274.17.12017.
Soeder KJ, Snedden SK, Cao W, Della Rocca GJ, Daniel KW, Luttrell LM, Collins S. The beta3-adrenergic receptor activates mitogen-activated protein kinase in adipocytes through a Gi-dependent mechanism. J Biol Chem. 1999 Apr 23;274(17):12017–12022.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

April 23, 1999

Volume

274

Issue

17

Start / End Page

12017 / 12022

Location

United States

Related Subject Headings

  • Receptors, Adrenergic, beta-3
  • Receptors, Adrenergic, beta
  • Protein Binding
  • Mice
  • Lipolysis
  • Humans
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Enzyme Activation
  • Dioxoles
  • Calcium-Calmodulin-Dependent Protein Kinases