Received for publication July 15, 2005.
Revised December 25, 2005.
Accepted for publication December 29, 2005.

TNF- Prevents Desensitization of Gs-coupled Receptors by Regulating GRK2 Association with the Plasma Membrane

Abstract

We have previously reported that IL-1 and TNF- increase expression and function of adenosine A_2A receptors (A_2AR), although the increased function is disproportionate to the increment in expression. We therefore studied the effect of TNF- on A_2AR function and desensitization in human monocytoid THP-1 cells. We observed that TNF- regulates activity of A_2AR and other G protein-coupled receptors (GPCRs) by altering their ligand-mediated desensitization. Pretreatment of resting cells with the A_2AR agonist CGS-21680 or the pan-adenosine receptor agonist NECA quickly desensitized cAMP responses to CGS-21680 re-stimulation, but TNF- treatment prevented A2AR desensitization. As expected, A_2AR occupancy induced translocation of GPCR kinase-2 (GRK2) to the plasma membrane (PM). Surprisingly, after TNF--treatment A_2AR occupancy not only failed to induce GRK2 translocation to PM but 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 following A_2AR 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 JNK, also a downstream effector in the SMase pathway, reversed TNF--mediated effects on GRK2 translocation and A_2AR desensitization. These results suggest a novel form of crosstalk 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 an SMase pathway-mediated mechanism.

Key words: Adenosine, Tumor necrosis factor, cAMP, Desensitization/uncoupling, GRKs, barrestins

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