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Biochem Biophys Res Commun. 2014 Jan 24;443(4):1195-9. doi: 10.1016/j.bbrc.2013.12.108. Epub 2013 Dec 28.

Nucleotidyl cyclase activity of soluble guanylyl cyclase in intact cells.

Author information

1
Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: baehre.heike@mh-hannover.de.
2
Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: kerstin.danker@evotec.com.
3
Institute of Cardiovascular Research, Bayer Healthcare, D-42096 Wuppertal, Germany. Electronic address: johannes-peter.stasch@bayer.com.
4
Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany; Core Unit Metabolomics, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: kaever.volkhard@mh-hannover.de.
5
Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: seifert.roland@mh-hannover.de.

Abstract

Soluble guanylyl cyclase (sGC) is activated by nitric oxide (NO) and generates the second messenger cyclic GMP (cGMP). Recently, purified sGC α1β1 has been shown to additionally generate the cyclic pyrimidine nucleotides cCMP and cUMP. However, since cyclic pyrimidine nucleotide formation occurred only the presence of Mn(2+) but not Mg(2+), the physiological relevance of these in vitro findings remained unclear. Therefore, we studied cyclic nucleotide formation in intact cells. We observed NO-dependent cCMP- and cUMP formation in intact HEK293 cells overexpressing sGC α1β1 and in RFL-6 rat fibroblasts endogenously expressing sGC, using HPLC-tandem mass spectrometry. The identity of cCMP and cUMP was unambiguously confirmed by HPLC-time-of-flight mass spectrometry. Our data indicate that cCMP and cUMP play second messenger roles and that Mn(2+) is a physiological sGC cofactor.

KEYWORDS:

Cyclic CMP; Cyclic GMP; Cyclic UMP; Manganese; Nitric oxide; Soluble guanylyl cyclase

PMID:
24380860
DOI:
10.1016/j.bbrc.2013.12.108
[Indexed for MEDLINE]
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