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Tumor Necrosis Factor- Prevents Desensitization of G_s-Coupled Receptors by Regulating GRK2 Association with the Plasma Membrane

Divisions of Clinical Pharmacology and Rheumatology, Department of Medicine, New York University School of Medicine, New York, New York

We have reported previously that interleukin-1 and tumor necrosis factor (TNF)- increase expression and function of adenosine A_2A receptors (A_2ARs), although the increased function is disproportionate to the increment in expression. We therefore studied the effect of TNF- on A_2A R function and desensitization in human monocytoid THP-1 cells. We observed that TNF- regulates activity of A_2A Rs and other G protein-coupled receptors (GPCRs) by altering their ligand-mediated desensitization. Pretreatment of resting cells with the A_2AR agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680) or the pan-adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine quickly desensitized cAMP responses to CGS 21680 restimulation, but TNF- treatment prevented A_2AR desensitization. As expected, A_2A R occupancy induced translocation of GPCR kinase-2 (GRK2) to the plasma membrane (PM). We were surprised to find that after TNF- treatment, A_2AR occupancy not only failed to induce GRK2 translocation to PM but also decreased GRK2 association with PM. TNF- altered GRK2 translocation in response to the -adrenergic receptor agonist isoproterenol in a similar manner. Similar to GRK2, -arrestin associated with PM after A_2A R stimulation in control cells but not in TNF--treated cells. C₂ -ceramide, a downstream mediator in the sphingomyelinase (SMase)-dependent pathway, mimicked the effect of TNF- on GRK2 translocation. Moreover, inhibitors of the SMases and an inhibitor of c-Jun NH₂-terminal kinase, also a downstream effector in the SMase pathway, reversed TNF--mediated effects on GRK2 translocation and A_2A R desensitization. These results suggest a novel form of cross-talk between TNF- receptors and GPCRs; TNF- enhances GPCR function by preventing agonist-induced desensitization of GPCRs by diminishing agonist-dependent recruitment of GRK2 and -arrestin to PM by a SMase pathway-mediated mechanism.

Address correspondence to: Dr. Bruce N. Cronstein, Department of Medicine, New York University School of Medicine, 550 First Ave., New York, NY 10016. E-mail: bruce.cronstein{at}nyumc.org

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