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Endogenous G Protein-Coupled Receptor Kinase 6 Triggers Homologous ß-Adrenergic Receptor Desensitization in Primary Uterine Smooth Muscle Cells

Laboratoire de Physiologie et Physiopathologie, Unité Mixte de Recherche 7079, Université P & M Curie, 75252 Paris Cedex 05, France

Address all correspondence and requests for reprints to: Dr. Joëlle Cohen-Tannoudji, Laboratoire de Physiologie et Physiopathologie, UMR 7079, Université P & M Curie, 4 Place Jussieu, 75252 Paris Cedex 05, France. E-mail: joelle.cohen-tannoudji{at}snv.jussieu.fr.

We previously reported that G protein-coupled receptor kinase (GRK) may contribute to ß-adrenergic receptor (ß-AR) uncoupling occurring just before parturition in rat uterine muscle (myometrium). To identify the GRK involved, we set up in this study a primary cell culture retaining the morphological and functional characteristics of myometrial tissue as well as the in vivo pattern of GRK expression (GRK2, GRK5, and GRK6). In this model, homologous ß-AR desensitization was assessed by an approximately 60% decrease in cAMP production to a subsequent challenge with the ß-agonist, isoproterenol. Desensitization was reduced by 36% with a GRK inhibitor, heparin, and by 31% with a protein kinase A in-hibitor, H89. Using antibodies known to specifically inhibit either GRK2/3 or GRK4–6 families, we demonstrated that only the GRK4–6 family mediated ß-AR desensitization. To discriminate between endogenous GRK5 and GRK6, we attempted to inhibit their action by introducing, into myometrial cells, kinase-dead dominant-negative mutants (^K215RGRK5 and ^K215RGRK6). Expression of ^K215RGRK6 increased by approximately 70% the cAMP response to isoproterenol without effect on forskolin stimulation. Conversely, expression of ^K215RGRK5 or ^K220RGRK2 had no effect on ß-adrenergic signaling. These results strongly suggest that endogenous GRK6 mediate homologous ß-AR desensitization in myometrial cells.

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