Delta Opioid Receptors Stimulate Akt-dependent Phosphorylation of C-jun in T Cells.
From: Department of Pharmacology, University of Tennessee Health Science Center, 38163, USA.
The Journal of pharmacology and experimental therapeutics
- Publish Date: Feb 2006
- ISSN: 0022-3565
- Volume: 316
- Issue: 2
- Pages: 933-9
- Medium: Print
- Language: English
- Citation (JAMA): Shahabi Nahid A, McAllen Kathy, Sharp Burt M, et al. Delta Opioid Receptors Stimulate Akt-dependent Phosphorylation of C-jun in T Cells.. J. Pharmacol. Exp. Ther. Feb 2006;316:933-9
Abstract
Activation of naive T cells markedly up-regulates the expression of delta opioid receptors (DORs). These receptors are bound by DOR peptides released by T cells, modulating T cell functions such as interleukin-2 production, cellular proliferation, and chemotaxis. Previous studies have shown that DOR agonists [e.g., [D-Ala(2)-D-Leu(5)]-enkephalin (DADLE)] modulate T cell antigen receptor signaling through mitogen-activated protein kinases (MAPKs; i.e., extracellular signal-regulated kinases 1 and 2) and that DORs directly induce phosphorylation of activating transcription factor-2 (implicated in cytokine gene transcription) and its association with the MAPK c-jun1 NH(2)-terminal kinase (JNK). Such observations suggest that DORs may induce the phosphorylation of c-jun. These experiments were performed to test this hypothesis and determine the potential roles of phosphoinositide 3-kinase (PI3K) and Akt (protein kinase B). DADLE (10(-10) to 10(-6) M) dose-dependently induced c-jun phosphorylation. This was blocked by pertussis toxin and the DOR-specific antagonist naltindole. Fluorescence flow cytometry showed that DADLE significantly stimulated c-jun phosphorylation by T cells. DADLE stimulated phosphorylation of membrane-associated Akt; wortmannin and LY294002 ([2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one]), specific inhibitors of PI3K, abolished the DADLE-induced phosphorylation of c-jun. Finally, inhibitors of Akt and JNK blocked DADLE-induced phosphorylation of c-jun. Thus, activated DORs directly stimulate c-jun phosphorylation through a PI3K-dependent pathway in T cells, apparently involving Akt. This implies that DORs activate JNK through a novel pathway dependent on PI3K and Akt, thereby regulating the function of activator protein-1 transcription complexes containing c-jun and other transcription partners.
Mesh Headings (Keywords): 1-Phosphatidylinositol 3-Kinase, Animals, Blotting, Western, Cell Membrane, Cells, Cultured, Dose-Response Relationship, Drug, Enkephalin, Leucine-2-Alanine, Enzyme Inhibitors, Flow Cytometry, JNK Mitogen-Activated Protein Kinases, Mice, Mice, Inbred BALB C, Phosphorylation, Proto-Oncogene Proteins c-akt, Receptors, Opioid, delta, Spleen, T-Lymphocytes
Check for Full Text / PubMed Unique Identifier (PMID): 16249373
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