Nucleotidyl cyclase activity of soluble guanylyl cyclase in intact cells

Bähre, Heike; Danker, Kerstin; Stasch, Johannes‐Peter; Kaever, Volkhard; Seifert, Roland

doi:10.1016/j.bbrc.2013.12.108

Cited by 40 publications

(28 citation statements)

References 32 publications

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“…When the enzyme is inhibited or defective, the ITP level is increased (3,29). Therefore, if hypoxia suppresses the activity of ITPase, sufficient ITP could accumulate for sGC to synthesize cIMP (2).…”

Section: Discussionmentioning

confidence: 99%

cIMP synthesized by sGC as a mediator of hypoxic contraction of coronary arteries

Chen

Zhang

Lei

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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. cIMP synthesized by sGC as a mediator of hypoxic contraction of coronary arteries. Am J Physiol Heart Circ Physiol 307: H328 -H336, 2014. First published June 6, 2014; doi:10.1152/ajpheart.00132.2014cGMP is considered the only mediator synthesized by soluble guanylyl cyclase (sGC) in response to nitric oxide (NO). However, purified sGC can synthesize several other cyclic nucleotides, including inosine 3=,5=-cyclic monophosphate (cIMP). The present study was designed to determine the role of cIMP in hypoxic contractions of isolated porcine coronary arteries. Vascular responses were examined by measuring isometric tension. Cyclic nucleotides were assayed by HPLC tandem mass spectroscopy. Rho kinase (ROCK) activity was determined by measuring the phosphorylation of myosin phosphatase target subunit 1 using Western blot analysis and an ELISA kit. The level of cIMP, but not that of cGMP, was elevated by hypoxia in arteries with, but not in those without, endothelium [except if treated with diethylenetriamine (DETA) NONOate]; the increases in cIMP were inhibited by the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ). Hypoxia (PO2: 25-30 mmHg) augmented contractions of arteries with and without endothelium if treated with DETA NONOate; these hypoxic contractions were blocked by ODQ. In arteries without endothelium, hypoxic augmentation of contraction was also obtained with exogenous cIMP. In arteries with endothelium, hypoxic augmentation of contraction was further enhanced by inosine 5=-triphosphate, the precursor for cIMP. The augmentation of contraction caused by hypoxia or cIMP was accompanied by increased phosphorylation of myosin phosphatase target subunit 1 at Thr 853 , which was prevented by the ROCK inhibitor Y-27632. ROCK activity in the supernatant of isolated arteries was stimulated by cIMP in a concentration-dependent fashion. These results demonstrate that cIMP synthesized by sGC is the likely mediator of hypoxic augmentation of coronary vasoconstriction, in part by activating ROCK. soluble guanylyl cyclase; inosine 3=,5=-cyclic monophosphate; hypoxic vasoconstriction; endothelium A PREVIOUS STUDY reported that acute hypoxia caused a rapid further increase in tension of contracted canine saphenous veins (31). Subsequent findings demonstrated that such a phenomenon, termed hypoxic augmentation of vasoconstriction (5, 15), occurs in a number of blood vessel types (5,7,8,15,21,23,25,26) contracted with norepinephrine (7, 8), phenylephrine (23), PGF 2␣ (15,25), and the TP receptor agonist U-46619 (21), indicating that it is not unique for a specific vasoconstrictor. It occurs in isolated coronary arteries with but not without endothelium (5,15,25,26). The phenomenon is not affected by bosentan, a blocker of endothelin receptors (5), but is prevented by inhibitors of nitric oxide (NO) synthase (5,15,25). Hypoxic augmentation also occurs in arteries without endothelium treated with an exogenous NO donor (5) However, hypoxic augmentation is not accompanied by changes in the intracellular leve...

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Section: Discussionmentioning

confidence: 99%

cIMP synthesized by sGC as a mediator of hypoxic contraction of coronary arteries

Chen

Zhang

Lei

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…Recently, a variety of cells and tissues have been shown to constitutively possess cUMP and cCMP (4,24). Mammalian soluble adenylyl and guanylyl cyclases are capable of synthesizing these cyclic nucleotides under some experimental conditions (3,25), and phosphodiesterase 3A and 3B degrade cUMP (47) while phosphodiesterase 7A1 inactivates cCMP (40). Multidrug resistance proteins export cUMP and cCMP out of the cell (34), raising the possibility that cellular production of pyrimidine cyclic nucleotides may result in their extracellular accumulation.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity of pulmonary endothelial cyclic nucleotide response toPseudomonas aeruginosaExoY infection

Morrow

Seifert

Kaever

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The fact that not only purine-but also pyrimidinenucleotides inhibited sGCa 1 b 1 was not surprising in view of the finding that UTP and CTP are also substrates for this enzyme both at the level of the purified enzyme and at the intact cell level Bähre et al, 2014). Purineand pyrimidine-nucleotides are also quite potent mAC inhibitors (Gille et al, 2004;Mou et al, 2005Mou et al, , 2006Suryanarayana et al, 2009;Hübner et al, 2011;Pinto et al, 2011), but currently it is not known whether mACs also accept UTP and CTP as substrates.…”

Section: Discussionmentioning

confidence: 99%

Structure/Activity Relationships of (M)ANT- and TNP-Nucleotides for Inhibition of Rat Soluble Guanylyl Cyclase α₁β₁

et al. 2014

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Soluble guanylyl cyclase (sGC) plays an important role in cardiovascular function and catalyzes formation of cGMP. sGC is activated by nitric oxide and allosteric stimulators and activators. However, despite its therapeutic relevance, the regulatory mechanisms of sGC are still incompletely understood. A major reason for this situation is that no crystal structures of active sGC have been resolved so far. An important step toward this goal is the identification of high-affinity ligands that stabilize an sGC conformation resembling the active, "fully closed" state. Therefore, we examined inhibition of rat sGCa 1 b 1 by 38 purine-and pyrimidinenucleotides with 2,4,6,-trinitrophenyl and (N-methyl)anthraniloyl substitutions at the ribosyl moiety and compared the data with that for the structurally related membranous adenylyl cyclases (mACs) 1, 2, 5 and the purified mAC catalytic subunits VC1:IIC2.

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Nucleotidyl cyclase activity of soluble guanylyl cyclase in intact cells

Cited by 40 publications

References 32 publications

cIMP synthesized by sGC as a mediator of hypoxic contraction of coronary arteries

cIMP synthesized by sGC as a mediator of hypoxic contraction of coronary arteries

Heterogeneity of pulmonary endothelial cyclic nucleotide response toPseudomonas aeruginosaExoY infection

Structure/Activity Relationships of (M)ANT- and TNP-Nucleotides for Inhibition of Rat Soluble Guanylyl Cyclase α₁β₁

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Nucleotidyl cyclase activity of soluble guanylyl cyclase in intact cells

Cited by 40 publications

References 32 publications

cIMP synthesized by sGC as a mediator of hypoxic contraction of coronary arteries

cIMP synthesized by sGC as a mediator of hypoxic contraction of coronary arteries

Heterogeneity of pulmonary endothelial cyclic nucleotide response toPseudomonas aeruginosaExoY infection

Structure/Activity Relationships of (M)ANT- and TNP-Nucleotides for Inhibition of Rat Soluble Guanylyl Cyclase α1β1

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Structure/Activity Relationships of (M)ANT- and TNP-Nucleotides for Inhibition of Rat Soluble Guanylyl Cyclase α₁β₁