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Molecular and Cellular Biology, October 2008, p. 6329-6341, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00482-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Novel Nuclear Signaling Pathway for Thromboxane A2 Receptors in Oligodendrocytes: Evidence for Signaling Compartmentalization during Differentiation{triangledown}

Fozia Mir and Guy C. Le Breton*

Department of Cellular and Molecular Pharmacology, University of Illinois at Chicago, College of Medicine, 835 South Wolcott Avenue (MC 868), Chicago, Illinois 60612-7343

Received 24 March 2008/ Returned for modification 21 April 2008/ Accepted 9 August 2008

The present study investigated G protein expression, localization, and functional coupling to thromboxane A2 receptors (TPRs) during oligodendrocyte (OLG) development. It was found that as OLGs mature, the expression levels of Gq increase while those of G13 decrease. In contrast, the expression levels of Gs, Go, and Gi do not change significantly. Localization studies revealed that Gq, G13, and Gi are present only in the extranuclear compartment, whereas Gs and Go are found in both the extranuclear and the nuclear compartments. Purification of TPR-G protein complexes demonstrated that TPRs couple to both Gq and G13 in the extranuclear compartment but only to Gs in the nuclear compartment. Furthermore, functional analysis revealed that stimulation of nuclear TPR in OLGs stimulates CREB phosphorylation and myelin basic protein transcription and increases survival. Collectively, these results demonstrate that (i) OLGs selectively modulate the expression of certain G proteins during development, (ii) G proteins are differentially localized in OLGs leading to subcellular compartmentalization, (iii) TPRs couple to Gq and G13 in the extranuclear compartment and to Gs only in the nucleus, (iv) mature OLGs have a functional nuclear TPR-Gs signaling pathway, and (v) nuclear TPR signaling can stimulate CREB phosphorylation and myelin gene transcription and increase cell survival. These findings represent a novel paradigm for selective modulation of G protein-coupled receptor-G protein signaling during cell development.

* Corresponding author. Mailing address: Department of Cellular and Molecular Pharmacology, University of Illinois at Chicago, College of Medicine, 835 South Wolcott Avenue (MC 868), Chicago, IL 60612-7343. Phone: (312) 996-4929. Fax: (312)-996-1225. E-mail: gcl{at}uic.edu

{triangledown} Published ahead of print on 18 August 2008.

Molecular and Cellular Biology, October 2008, p. 6329-6341, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00482-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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