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Oligodeoxynucleotides Antisense to mRNA Encoding Protein Kinase A, Protein Kinase C, and β-Adrenergic Receptor Kinase Reveal Distinctive Cell-Type-Specific Roles in agonist-Induced Desensitization
Meiling Shih and Craig C. Malbon
Proceedings of the National Academy of Sciences of the United States of America
Vol. 91, No. 25 (Dec. 6, 1994), pp. 12193-12197
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/2366304
Page Count: 5
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The roles of three protein kinases, cyclic AMP-dependent protein kinase (protein kinase A), protein kinase C, and β-adrenergic receptor kinase (βARK), implicated in agonist-induced desensitization of guanine nucleotide-binding protein (G-protein)-coupled receptors were explored in four different cell lines after 48 hr of incubation with oligodeoxynucleotides antisense to the mRNA encoding each kinase. Desensitization of β2-adrenergic receptors was analyzed in cell types in which the activities of the endogenous complement of protein kinases A and C and βARK were distinctly different. Protein kinase A was necessary for desensitization of rat osteosarcoma cells (ROS 17/2.8), whereas the contribution of βARK to desensitization was insignificant. In Chinese hamster ovary cells that stably express β2-adrenergic receptors and in smooth muscle cells (DDT1MF-2), oligodeoxynucleotides antisense to βARK mRNA nearly abolished desensitization, whereas oligodeoxynucleotides antisense to protein kinase A mRNA attenuated desensitization to a lesser extent. In human epidermoid carcinoma cells (A-431), oligodeoxynucleotides antisense to either protein kinase A mRNA or βARK mRNA attenuated agonist-induced desensitization, providing a third scenario in which two kinases constitute the basis for agonist-induced desensitization. In sharp contrast, oligodeoxynucleotides antisense to protein kinase C mRNA were found to enhance rather than attenuate desensitization in DDT1MF-2 and A-431 cell lines, demonstrating counterregulation between prominent protein kinases in desensitization. Using antisense oligodeoxynucleotides to "knock out" target protein kinases in vivo, we reveal distinctive cell-type-specific roles of protein kinase A, protein kinase C, and βARK in agonist-induced desensitization.
Proceedings of the National Academy of Sciences of the United States of America © 1994 National Academy of Sciences