ATP potentiates competitive inhibition of guanylyl cyclase A and B by the staurosporine analog, Gö6976: Reciprocal regulation of ATP and GTP binding

Jerid W Robinson, Lincoln R Potter

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9 Citations (Scopus)

Abstract

Natriuretic peptides and ATP activate and Gö6976 inhibits guanylyl cyclase (GC)-A and GC-B. Here, the mechanism of inhibition was determined. Gö6976 progressively increased the Michaelis-Menten constant and decreased the Hill coefficient without reducing the maximal velocity of GC-A and GC-B. In the presence of 1 mM ATP, the K i was 1 μM for both enzymes. Inhibition of GC-B was minimal in the absence of ATP, and 1 mM ATP increased the inhibition 4-fold. In a reciprocal manner, 10 μM Gö6976 increased the potency of ATP for GC-B 4-fold. In contrast to a recent study (Duda, T., Yadav, P., and Sharma, R. K. (2010) FEBS J. 277, 2550-2553), neither staurosporine nor Gö6976 activated GC-A or GC-B. This is the first study to show that Gö6976 reduces GTP binding and the first demonstration of a competitive inhibitor of a receptor guanylyl cyclase. We conclude that Gö6976 reduces GTP binding to the catalytic site of GC-A and GC-B and that ATP increases the magnitude of the inhibition.

Original languageEnglish (US)
Pages (from-to)33841-33844
Number of pages4
JournalJournal of Biological Chemistry
Volume286
Issue number39
DOIs
StatePublished - Oct 30 2011

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Staurosporine
Guanylate Cyclase
Guanosine Triphosphate
Adenosine Triphosphate
Guanylate Cyclase-Coupled Receptors
Natriuretic Peptides
atrial natriuretic factor receptor A
Catalytic Domain
Demonstrations
Enzymes

Cite this

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title = "ATP potentiates competitive inhibition of guanylyl cyclase A and B by the staurosporine analog, G{\"o}6976: Reciprocal regulation of ATP and GTP binding",
abstract = "Natriuretic peptides and ATP activate and G{\"o}6976 inhibits guanylyl cyclase (GC)-A and GC-B. Here, the mechanism of inhibition was determined. G{\"o}6976 progressively increased the Michaelis-Menten constant and decreased the Hill coefficient without reducing the maximal velocity of GC-A and GC-B. In the presence of 1 mM ATP, the K i was 1 μM for both enzymes. Inhibition of GC-B was minimal in the absence of ATP, and 1 mM ATP increased the inhibition 4-fold. In a reciprocal manner, 10 μM G{\"o}6976 increased the potency of ATP for GC-B 4-fold. In contrast to a recent study (Duda, T., Yadav, P., and Sharma, R. K. (2010) FEBS J. 277, 2550-2553), neither staurosporine nor G{\"o}6976 activated GC-A or GC-B. This is the first study to show that G{\"o}6976 reduces GTP binding and the first demonstration of a competitive inhibitor of a receptor guanylyl cyclase. We conclude that G{\"o}6976 reduces GTP binding to the catalytic site of GC-A and GC-B and that ATP increases the magnitude of the inhibition.",
author = "Robinson, {Jerid W} and Potter, {Lincoln R}",
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T1 - ATP potentiates competitive inhibition of guanylyl cyclase A and B by the staurosporine analog, Gö6976

T2 - Reciprocal regulation of ATP and GTP binding

AU - Robinson, Jerid W

AU - Potter, Lincoln R

PY - 2011/10/30

Y1 - 2011/10/30

N2 - Natriuretic peptides and ATP activate and Gö6976 inhibits guanylyl cyclase (GC)-A and GC-B. Here, the mechanism of inhibition was determined. Gö6976 progressively increased the Michaelis-Menten constant and decreased the Hill coefficient without reducing the maximal velocity of GC-A and GC-B. In the presence of 1 mM ATP, the K i was 1 μM for both enzymes. Inhibition of GC-B was minimal in the absence of ATP, and 1 mM ATP increased the inhibition 4-fold. In a reciprocal manner, 10 μM Gö6976 increased the potency of ATP for GC-B 4-fold. In contrast to a recent study (Duda, T., Yadav, P., and Sharma, R. K. (2010) FEBS J. 277, 2550-2553), neither staurosporine nor Gö6976 activated GC-A or GC-B. This is the first study to show that Gö6976 reduces GTP binding and the first demonstration of a competitive inhibitor of a receptor guanylyl cyclase. We conclude that Gö6976 reduces GTP binding to the catalytic site of GC-A and GC-B and that ATP increases the magnitude of the inhibition.

AB - Natriuretic peptides and ATP activate and Gö6976 inhibits guanylyl cyclase (GC)-A and GC-B. Here, the mechanism of inhibition was determined. Gö6976 progressively increased the Michaelis-Menten constant and decreased the Hill coefficient without reducing the maximal velocity of GC-A and GC-B. In the presence of 1 mM ATP, the K i was 1 μM for both enzymes. Inhibition of GC-B was minimal in the absence of ATP, and 1 mM ATP increased the inhibition 4-fold. In a reciprocal manner, 10 μM Gö6976 increased the potency of ATP for GC-B 4-fold. In contrast to a recent study (Duda, T., Yadav, P., and Sharma, R. K. (2010) FEBS J. 277, 2550-2553), neither staurosporine nor Gö6976 activated GC-A or GC-B. This is the first study to show that Gö6976 reduces GTP binding and the first demonstration of a competitive inhibitor of a receptor guanylyl cyclase. We conclude that Gö6976 reduces GTP binding to the catalytic site of GC-A and GC-B and that ATP increases the magnitude of the inhibition.

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