guanylyl-imidodiphosphate and phorbol-12-13-didecanoate

Treatment of isolated rat enterocytes with the halogenated insecticide lindane (the gamma-isomer of hexachlorocyclohexane, HCCH) did not modify the general membrane fluidity (as estimated by a fluorescence polarization technique) nor the guanine nucleotide binding regulatory protein Gs (as studied by both ADP-ribosylation of its alpha subunit by cholera toxin and Gpp[NH]p stimulation of membrane adenylate cyclase activity). However, lindane decreased in a dose-dependent manner the effect of the diterpene forskolin on direct activation of the adenylate cyclase catalytic subunit. After 5 min of cell treatment with 0.5 mM lindane, the maximal stimulatory effect of forskolin (at 100 microM) decreased by about 50%. There was a certain degree of specificity since delta-HCCH was indeed more potent, whereas dieldrin and endrin (non-lindane related halogenated compounds) behaved as lindane, and alpha- and beta-HCCH were poorly efficient on the inhibition of forskolin stimulation of adenylate cyclase activity. A similar effect of lindane was observed on receptor-stimulated cyclic AMP accumulation by using vasoactive intestinal peptide instead of forskolin. The results on a non-receptor mediated effect of lindane on the adenylate cyclase catalytic subunit itself could be related to: (i) alterations of membrane microdomains surrounding this and other integral proteins which would result in modifications of their activities; and/or (ii) a reciprocal relation between the two main routes of signal transduction so that the activation of protein kinase C (or other Ca(2+)-dependent protein kinases) by lindane would lead to phosphorylation of the adenylate cyclase catalytic subunit.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 1-Methyl-3-isobutylxanthine; Adenosine Diphosphate Ribose; Adenylyl Cyclases; Animals; Autoradiography; Cell Membrane; Cholera Toxin; Colforsin; Cyclic AMP; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Hexachlorocyclohexane; Intestinal Mucosa; Jejunum; Kinetics; Male; Membrane Proteins; Phorbol Esters; Phosphorus Radioisotopes; Rats; Rats, Wistar; Tetradecanoylphorbol Acetate; Vasoactive Intestinal Peptide