An intracellular adenine nucleotide binding site inhibits guanyly cyclase C by a guanine nucleotide-dependent mechanism

Biochemistry
S J Parkinson, S A Waldman

Abstract

Guanylyl cyclase C (GCC), the receptor for the Escherichia coli heat-stable enterotoxin (ST), is inhibited by 2-substituted adenine nucleotides in an allosteric fashion. In confluent cultures of Caco-2 intestinal epithelial cells, extracellular 2-methylthioadenosine triphosphate (2MeSATP) had no effect on basal or ST-stimulated cyclic GMP (cGMP) accumulation. However, this nucleotide inhibited cGMP accumulation in digitonin-permeabilized Caco-2 human colon carcinoma cells, demonstrating that allosteric inhibition of GCC by adenine nucleotides is mediated by an intracellular adenine nucleotide binding site rather than purinergic receptors. The role of guanine nucleotides in the regulation of GCC by adenine nucleotides was examined. Increasing GTP concentrations from 5 to 100 microM increased the potency of 2MeSATP inhibition of GCC 20-fold, with a shift in the Ki from 447 to 22 microM, respectively. Also, the hydrolysis-resistant analogue, guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS), supported 2MeSATP inhibition of GCC with a potency which was 10-fold greater than GTP. In addition, GTP alone, in the absence of adenine nucleotides and at concentrations greater than 1 mM, inhibited GCC through a mechanism convergent with 2MeSA...Continue Reading

References

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Citations

May 3, 2002·European Journal of Biochemistry·Inez Ruiz-StewartScott A Waldman
Dec 20, 2003·Proceedings of the National Academy of Sciences of the United States of America·I Ruiz-StewartS A Waldman
May 23, 2015·The Journal of Infectious Diseases·Marcel J C BijveldsJoris H De Maeyer
Feb 19, 1998·Archives of Biochemistry and Biophysics·M J AlfonzoR G de Alfonzo
Jul 28, 2010·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Roland LudwigLo Gorton
Jan 6, 2007·Organic & Biomolecular Chemistry·Andrew J WilsonAndrew D Hamilton
Jun 7, 2005·The Journal of Pharmacology and Experimental Therapeutics·Shiva KazerounianScott A Waldman
Dec 5, 2009·Molecular and Cellular Biochemistry·Nirmalya BasuSandhya S Visweswariah
May 4, 1999·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·W ZhangS A Waldman

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