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http://purl.uniprot.org/citations/21366551http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/21366551http://www.w3.org/2000/01/rdf-schema#comment"

Background and purpose

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) decrease vascular volume and pressure by activating guanylyl cyclase-A (GC-A). C-type natriuretic peptide (CNP) activation of guanylyl cyclase-B (GC-B) stimulates long bone growth. This study investigated the effects of the indolocarbazole, Gö6976, on the guanylyl cyclase activity of GC-A and GC-B as a first step towards developing small molecule regulators of these enzymes.

Experimental approach

Whole cell cGMP concentrations or ³²P-cGMP accumulation in membrane preparations measured the effects of indolocarbazoles on the enzymatic activity GC-A and GC-B from transfected 293T or endogenously expressing 3T3-L1 cells.

Key results

Gö6976 blocked cellular CNP-dependent cGMP elevations in 293T-GC-B cells. The t(½) for Gö6976 inhibition was 7 s and IC₅₀ was 380 nM. Gö6976 increased the EC₅₀ for CNP 4.5-fold, but increasing the CNP concentration did not overcome the inhibition. Half of the inhibition was lost 1 h after removal of Gö6976 from the medium. Cellular exposure to Gö6976 reduced basal and natriuretic peptide-dependent, but not detergent-dependent, GC-A and GC-B activity. Inhibition was also observed when Gö6976 was added directly to the cyclase assay. A constitutively phosphorylated form of GC-B was similarly inhibited.

Conclusions and implications

These data demonstrate that Gö6976 potently, rapidly and reversibly inhibited GC-A and GC-B via a process that did not require intact cells, known phosphorylation sites or inactivation of all catalytic sites. This is the first report of an intracellular inhibitor of a transmembrane guanylyl cyclase and the first report of a non-kinase target for Gö6976."xsd:string
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http://purl.uniprot.org/citations/21366551http://purl.uniprot.org/core/author"Lou X."xsd:string
http://purl.uniprot.org/citations/21366551http://purl.uniprot.org/core/author"Potter L.R."xsd:string
http://purl.uniprot.org/citations/21366551http://purl.uniprot.org/core/author"Robinson J.W."xsd:string
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http://purl.uniprot.org/citations/21366551http://purl.uniprot.org/core/name"Br J Pharmacol"xsd:string
http://purl.uniprot.org/citations/21366551http://purl.uniprot.org/core/pages"499-506"xsd:string
http://purl.uniprot.org/citations/21366551http://purl.uniprot.org/core/title"The indolocarbazole, Go6976, inhibits guanylyl cyclase-A and -B."xsd:string
http://purl.uniprot.org/citations/21366551http://purl.uniprot.org/core/volume"164"xsd:string
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