Document Detail

Growth of S49 cells in low concentrations of beta-adrenergic agonists causes desensitization.
MedLine Citation:
PMID:  2550779     Owner:  NLM     Status:  MEDLINE    
Epinephrine at concentrations approximating circulating levels in resting subjects produced significant desensitization in wild type S49 lymphoma cells after long term treatment. Desensitization by such low levels of catecholamines was measured by examining subsequent responses of the cells to higher agonist concentrations and was quantified by comparing the integral cAMP accumulations with time in naive and epinephrine-treated cells challenged with the higher epinephrine concentrations. The cells were significantly desensitized after 8 hr of treatment with 3 nM epinephrine or 3 nM terbutaline and were essentially maximally refractory after 24 hr. The 3 nM epinephrine treatment resulted in a small right shift of the EC50. Responses to epinephrine were partially restored by incubating desensitized cells for 8 hr or longer in growth medium that was free of epinephrine. The attenuation of cAMP responses was largely specific, in that the decrease in the response to prostaglandin was small and the response to forskolin was unchanged. This, together with small increases in cAMP destruction in cell-free preparations from treated cells, suggested that higher phosphodiesterase activity contributed in a minor way to the desensitization. However, the response of the adenylate cyclase system to epinephrine was dramatically attenuated, and very significant changes in the properties of the beta-adrenergic receptors were also obvious. That is, the number of binding sites for epinephrine was reduced by about 65% while the number of sites for [125I]iodocyanopindolol was unchanged. The affinity for the radioactive ligand was significantly reduced. Wild type S49 cells remained viable after several days of continuous treatment with 3 nM epinephrine or terbutaline but responded to subsequent increases in cellular cAMP levels with the expected growth arrest and cytolysis. Involvement of cAMP-dependent protein kinase in this type of desensitization was suggested by the observation that S49 kincells were not desensitized by long term incubation with 3 nM epinephrine. Further, low concentrations of dibutyryl cAMP mimicked the effect of low level epinephrine treatment. We conclude that circulating levels of epinephrine in intact animals are sufficiently high to cause desensitization in cells with sensitivities to the catecholamines in the same range as that of the S49 lymphoma cell in vitro. We would predict that cells with those characteristics would always be at least partially desensitized in vivo.
R Barber; T J Goka; R W Butcher
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular pharmacology     Volume:  36     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  1989 Sep 
Date Detail:
Created Date:  1989-10-26     Completed Date:  1989-10-26     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  459-64     Citation Subset:  IM    
Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston 77225.
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MeSH Terms
3',5'-Cyclic-AMP Phosphodiesterases / metabolism
Adenylate Cyclase / metabolism
Alprostadil / pharmacology
Cyclic AMP / metabolism
Epinephrine / pharmacology*
Forskolin / pharmacology
Protein Kinases / metabolism
Receptors, Adrenergic, beta / metabolism*
Terbutaline / pharmacology*
Time Factors
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/Receptors, Adrenergic, beta; 23031-25-6/Terbutaline; 51-43-4/Epinephrine; 60-92-4/Cyclic AMP; 66428-89-5/Forskolin; 745-65-3/Alprostadil; EC 2.7.-/Protein Kinases; EC',5'-Cyclic-AMP Phosphodiesterases; EC Cyclase

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