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Vol. 54, Issue 1, 44-49, July 1998

Phosphorylation and Functional Desensitization of the alpha 2A-Adrenergic Receptor by Protein Kinase C

Mei Liang, Margaret G. Eason, Elizabeth A. Jewell-Motz, Mark A. Williams, Cheryl T. Theiss, Gerald W. Dorn, II, and Stephen B. Liggett

Departments of Pathology (M.L. G.W.D., S.B.L.), Medicine (M.G.E., E.A.J., C.T.T., G.W.D., S.B.L.), and Pharmacology (G.W.D., M.A.W., S.B.L.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0564

We have investigated the potential for protein kinase C (PKC) to phosphorylate and desensitize the alpha 2A-adrenergic receptor (alpha 2AAR). In whole-cell phosphorylation studies, recombinantly expressed human alpha 2AAR displayed an increase in phosphorylation after short-term exposure to 100 nM phorbol 12-myristate-13-acetate (PMA) that was blocked by preincubation with a PKC inhibitor. This increase in receptor phosphorylation over basal amounted to 172 ± 40% in COS-7 cells and 201 ± 40% in Chinese hamster ovary cells. In permanently transfected Chinese hamster fibroblast cells, PKC activation by brief exposure of the cells to PMA resulted in a marked desensitization of alpha 2AAR function, amounting to a 68 ± 4% decrease in the maximal agonist (UK14304)-stimulated intracellular calcium release. Such desensitization was blocked by the PKC inhibitor bisindolylmaleimide I and was not evoked by an inactive phorbol ester. The desensitization of this agonist response was not caused by PKC-mediated augmentation of G protein-coupled receptor kinase activity, because PMA-promoted desensitization of a mutated alpha 2AAR that lacked G protein-coupled receptor kinase phosphorylation sites was identical to that of wild-type alpha 2AAR. To test whether PKC phosphorylation is a mechanism by which alpha 2AAR can be regulated by other receptors, the alpha 1bAR was co-expressed with the alpha 2AAR in Chinese hamster ovary cells. Upon selective activation of alpha 1bAR, the function of alpha 2AAR underwent a 53 ± 5% desensitization. Thus, cellular events that result in PKC activation promote phosphorylation of the alpha 2AAR and lead to substantial desensitization of receptor function. This heterologous regulation also represents a mechanism by which rapid crosstalk between the alpha 2AAR and other receptors can occur.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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