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

Jun 18, 2003Endocrinology

Natural kinase 6 causes reduced response of beta-adrenergic receptors in uterine muscle cells

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Abstract

An approximately 70% increase in cAMP response to isoproterenol was observed when (K215R)GRK6 was expressed in myometrial cells.

G protein-coupled receptor kinase (GRK) may contribute to beta-adrenergic receptor uncoupling in rat uterine muscle before parturition.
Homologous beta-adrenergic receptor desensitization was indicated by a 60% decrease in cAMP production in response to isoproterenol.
A GRK inhibitor reduced desensitization by 36%, while a protein kinase A inhibitor reduced it by 31%.
Only the GRK4-6 family of kinases was found to mediate beta-adrenergic receptor desensitization.
Endogenous GRK6 specifically appears to mediate homologous beta-adrenergic receptor desensitization in myometrial cells.

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We previously reported that G protein-coupled receptor kinase (GRK) may contribute to beta-adrenergic receptor (beta-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 beta-AR desensitization was assessed by an approximately 60% decrease in cAMP production to a subsequent challenge with the beta-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 beta-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 ((K215R)GRK5 and (K215R)GRK6). Expression of (K215R)GRK6 increased by approximately 70% the cAMP response to isoproterenol without effect on forskolin stimulation. Conversely, expression of (K215R)GRK5 or (K220R)GRK2 had no effect on beta-adrenergic signaling. These results strongly suggest that endogenous GRK6 mediate homologous beta-AR desensitization in myometrial cells.

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

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