Direct interactions with Gαi and Gβγ mediate nongenomic signaling by estrogen receptor α

Premlata Kumar, Qian Wu, Ken L. Chambliss, Ivan S. Yuhanna, Susanne M. Mumby, Chieko Mineo, Gregory G. Tall, Philip W. Shaul

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Estrogen induces G protein-dependent nongenomic signaling in a variety of cell types via the activation of a plasma membrane-associated subpopulation of estrogen receptor α (ERα). Using pull-down experiments with purified recombinant proteins, we now demonstrate that ERα binds directly to Gαi and Gβγ. Mutagenesis and the addition of blocking peptide reveals that this occurs via amino acids 251-260 and 271-595 of ERα, respectively. Studies of ERα complexed with heterotrimeric G proteins further show that estradiol causes the release of both Gαi and Gβγ without stimulating GTP binding to Gαi. Moreover, in COS-7 cells, the disruption of ERα-Gαi interaction by deletion mutagenesis of ERα or expression of blocking peptide, as well as Gβγ sequestration with β-adrenergic receptor kinase C terminus, prevents nongenomic responses to estradiol including src and erk activation. In endothelial cells, the disruption of ERα-Gαi interaction prevents estradiol-induced nitric oxide synthase activation and the resulting attenuation of monocyte adhesion that contributes to estrogen-related cardiovascular protection. Thus, through direct interactions, ERα mediates a novel mechanism of G protein activation that provides greater diversity of function of both the steroid hormone receptor and G proteins.

Original languageEnglish (US)
Pages (from-to)1370-1380
Number of pages11
JournalMolecular Endocrinology
Volume21
Issue number6
DOIs
StatePublished - Jun 2007

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Estrogen Receptors
GTP-Binding Proteins
Estradiol
Mutagenesis
Estrogens
Heterotrimeric GTP-Binding Proteins
Peptides
Steroid Receptors
COS Cells
Guanosine Triphosphate
Recombinant Proteins
Nitric Oxide Synthase
Adrenergic Receptors
Monocytes
Phosphotransferases
Endothelial Cells
Cell Membrane
Hormones
Amino Acids

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Direct interactions with Gαi and Gβγ mediate nongenomic signaling by estrogen receptor α. / Kumar, Premlata; Wu, Qian; Chambliss, Ken L.; Yuhanna, Ivan S.; Mumby, Susanne M.; Mineo, Chieko; Tall, Gregory G.; Shaul, Philip W.

In: Molecular Endocrinology, Vol. 21, No. 6, 06.2007, p. 1370-1380.

Research output: Contribution to journalArticle

Kumar, Premlata ; Wu, Qian ; Chambliss, Ken L. ; Yuhanna, Ivan S. ; Mumby, Susanne M. ; Mineo, Chieko ; Tall, Gregory G. ; Shaul, Philip W. / Direct interactions with Gαi and Gβγ mediate nongenomic signaling by estrogen receptor α. In: Molecular Endocrinology. 2007 ; Vol. 21, No. 6. pp. 1370-1380.
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