Protein kinase C activators sensitize cyclic AMP accumulation by intact 1321N1 human astrocytoma cells

Robert A. Johnson, Myron Lee Toews

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Abstract

Pretreatment of 1321N1 human astrocytoma cells with phorbol 12-myristate-13-acetate or other activators of protein kinase C led to 2.5- to 5-fold increases (sensitization) in subsequent stimulation by forskolin of intracellular cyclic AMP accumulation. These compounds caused much smaller or no increases in receptor-mediated stimulation of cyclic AMP accumulation induced by isoproterenol and by prostaglandin E1. Carbachol and histamine, agonists acting at receptors coupled to polyphosphoinositide turnover in these cells, induced less sensitization of subsequent stimulation by forskolin but greater sensitization of stimulation by isoproterenol and by prostaglandin E1. The specificities of various analogs of phorbol 12-myristate-13-acetate, for induction of sensitization of forskolin stimulation were consistent with involvement of protein kinase C. The effects of protein kinase inhibitors and of down-regulation of protein kinase C activity also indicated involvement of protein kinase C in sensitization of forskolin stimulation, although additional mechanisms are likely to be involved in sensitization of isoproterenol stimulation. Neither pertussis toxin pretreatment nor inclusion of isobutylmethylxanthine during assays of cyclic AMP accumulation were able to prevent or mimic these sensitization phenomena, suggesting that the primary site of modification responsible for sensitization is neither the inhibitory guanine nucleotide-binding protein nor cyclic AMP phosphodiesterase. Sensitization was only observed in assays with intact cells. These results together with those from our previous study describing protein kinase C-mediated desensitization of broken cell adenylate cyclase activity, indicate that activation of protein kinase C leads to multiple changes in the receptor-stimulated adenylate cyclase signal transduction pathway of these cells.

Original languageEnglish (US)
Pages (from-to)296-303
Number of pages8
JournalMolecular pharmacology
Volume37
Issue number2
StatePublished - Jan 1 1990

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Astrocytoma
Cyclic AMP
Protein Kinase C
Colforsin
Isoproterenol
Alprostadil
Adenylyl Cyclases
Acetates
Histamine Agonists
Phosphatidylinositol Phosphates
Guanine Nucleotides
Pertussis Toxin
Phosphoric Diester Hydrolases
Carbachol
Protein Kinase Inhibitors
Signal Transduction
Carrier Proteins
Down-Regulation

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Protein kinase C activators sensitize cyclic AMP accumulation by intact 1321N1 human astrocytoma cells. / Johnson, Robert A.; Toews, Myron Lee.

In: Molecular pharmacology, Vol. 37, No. 2, 01.01.1990, p. 296-303.

Research output: Contribution to journalArticle

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