A novel nuclear signaling pathway for thromboxane A2 receptors in oligodendrocytes: evidence for signaling compartmentalization during differentiation.
The present study investigated G protein expression, localization, and functional coupling to thromboxane A(2) receptors (TPRs) during oligodendrocyte (OLG) development. It was found that as OLGs mature, the expression levels of G(q) increase while those of G(13) decrease. In contrast, the expression levels of G(s), G(o), and G(i) do not change significantly. Localization studies revealed that G(q), G(13), and G(i) are present only in the extranuclear compartment, whereas G(s) and G(o) are found in both the extranuclear and the nuclear compartments. Purification of TPR-G protein complexes demonstrated that TPRs couple to both G(q) and G(13) in the extranuclear compartment but only to G(s) 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 G(q) and G(13) in the extranuclear compartment and to G(s) only in the nucleus, (iv) mature OLGs have a functional nuclear TPR-G(s) 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.
Mir
Fozia
F
Department of Cellular and Molecular Pharmacology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612-7343, USA.
Le Breton
Guy C
GC
D000818:Animals; D002451:Cell Compartmentation; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000302:isolation & purification / Q000378:metabolism; D005786:Gene Expression Regulation; D042541:Intracellular Space / Q000378:metabolism; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology* / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013928:Thromboxane A2 / Q000096:biosynthesis
D017362:Cyclic AMP Response Element-Binding Protein; D004676:Myelin Basic Protein; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2; D000242:Cyclic AMP; D019204:GTP-Binding Proteins