Activation of cAMP-Dependent Protein Kinase is Required for Heterologous Desensitization of Adenylyl Cyclase in S49 Wild-Type Lymphoma Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 85; no. 5; pp. 1442 - 1446
• Main Authors: Clark, Richard B., Kunkel, Mark W., Friedman, Jacqueline, Goka, Thomas J., Johnson, John A.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01-03-1988; National Acad Sciences
• Subjects: adenylate cyclase; Adenylyl Cyclases - metabolism; Animals; B cell lymphoma; Biological and medical sciences; Bucladesine - pharmacology; Cell lines; Cell physiology; Colforsin - pharmacology; Cyclic AMP - physiology; Cyclic nucleotides; Epinephrine - pharmacology; Fundamental and applied biological sciences. Psychology; Hormonal regulation; Hormones; Inurement; Low concentrations; Lymphoma; Mice; Molecular and cellular biology; Phosphorylation; Pretreatment; protein kinase; Protein Kinases - physiology; Receptors; Receptors, Adrenergic, beta - physiology; Tumor Cells, Cultured - enzymology; Epinephrine; Adenylate cyclase; Desensitization; Protein kinase; Established cell line; Activation; Lymphoma; β-Adrenergic receptor
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.85.5.1442

We report here that, contrary to previously reported findings, treatment of S49 wild-type (WT) lymphoma cells with 0-50 nM epinephrine resulted in a heterologous desensitization of adenylyl cyclase (EC 4.6.1.1)--that is, epinephrine and prostaglandin E1 (PGE1) stimulations of adenylyl cyclase were reduced. Observation of this heterologous desensitization required the assay of adenylyl cyclase with submillimolar concentrations of Mg2+ and low concentrations of epinephrine. Also, whereas previously there had been no evidence for any role of cAMP-dependent protein kinase in the desensitization of the WT β -adrenergic receptor, our data comparing the characteristics of the desensitization in WT, kin-, and cyc- lymphoma cells [where kin- and cyc- refer to variants of S49 WT cells lacking cAMP-dependent protein kinase activity (kin-) and the α subunit of the stimulatory guanine nucleotide-binding regulatory protein (cyc-) now suggest that cAMP-dependent protein kinase mediates the heterologous desensitization of adenylyl cyclase. Specifically, we found that only the WT cells exhibited epinephrine-induced heterologous desensitization. The kin- and cyc- cells exhibited only homologous desensitization, and much higher concentrations of epinephrine were required to elicit the homologous desensitization in the variants relative to the heterologous desensitization of the WT. Treatment of WT and cyc- cells with dibutyryl cAMP or treatment of WT with forskolin or PGE1 caused the heterologous desensitization of adenylyl cyclase, indicating that neither receptor occupancy nor activation of adenylyl cyclase was necessary for the heterologous desensitization.