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Stimulation of β 2-adrenergic receptors inhibits calcineurin activity in CD4 + T cells via PKA–AKAP interaction

Stimulation of β 2-adrenergic receptors inhibits calcineurin activity in CD4 + T cells via PKA–AKAP interaction,10.1016/j.bbi.2010.07.248,Brain Behavi

Stimulation of β 2-adrenergic receptors inhibits calcineurin activity in CD4 + T cells via PKA–AKAP interaction   (Citations: 2)
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The sympathetic nervous system (SNS) is able to modulate immune functions via adrenoceptor-dependent mechanisms. Activation of β2-adrenergic receptors (AR) on CD4+ T lymphocytes has been shown to inhibit Th1-cytokine production and cell proliferation. Here, we investigated the role of the calcium/calmodulin-dependent protein phosphatase calcineurin (CaN), a key element of the T cell receptor (TCR)-signaling pathway, in β2-AR-mediated suppression of T cell function. Purified rat splenic CD4+ T cells were stimulated with anti-CD3/anti-CD28 in presence or absence of the β2-AR agonist terbutaline (TERB). Treatment with TERB induced a dose-dependent inhibition of cellular CaN activity, along with a reduction in IL-2 and IFN-γ production, and T cell proliferation. Co-administration of the β-AR antagonist nadolol abolished these effects. Blockade of the cAMP-dependent protein kinase A (PKA) with the inhibitor H-89 completely prevented TERB-induced CaN inhibition. However, a receptor-independent rise in the second messenger cAMP was not sufficient to suppress CaN activity. Disruption of the interaction between PKA and A-kinase anchoring protein (AKAP) by the inhibitor peptide St-Ht31 fully blocked TERB-induced CaN inhibition, demonstrating that PKA–AKAP interaction is essential for the β2-AR-mediated CaN inhibition. Taken together, this study provides evidence for a link between the β2-AR and TCR signaling pathways since expression of IL-2 and IFN-γ in activated T cells largely depends on dephosphorylation of the transcription factor NFAT by CaN, and identifies a novel intracellular mechanism that can lead to downregulation of T cell function after SNS activation.
Journal: Brain Behavior and Immunity - BRAIN BEHAV IMMUN , vol. 25, no. 1, pp. 59-66, 2011
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