scholarly journals Oxidation of cysteine 117 stimulates constitutive activation of the type Iα cGMP-dependent protein kinase

2018 ◽  
Vol 293 (43) ◽  
pp. 16791-16802 ◽  
Author(s):  
Jessica L. Sheehe ◽  
Adrian D. Bonev ◽  
Anna M. Schmoker ◽  
Bryan A. Ballif ◽  
Mark T. Nelson ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Specific Substrate ◽  
Type I ◽  
Amino Acid Residues ◽  
Dependent Protein Kinase ◽  
Constitutive Activation ◽  
Channel Characteristics ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

The type I cGMP-dependent protein kinase (PKG I) is an essential regulator of vascular tone. It has been demonstrated that the type Iα isoform can be constitutively activated by oxidizing conditions. However, the amino acid residues implicated in this phenomenon are not fully elucidated. To investigate the molecular basis for this mechanism, we studied the effects of oxidation using recombinant WT, truncated, and mutant constructs of PKG I. Using an in vitro assay, we observed that oxidation with hydrogen peroxide (H2O2) resulted in constitutive, cGMP-independent activation of PKG Iα. PKG Iα C42S and a truncation construct that does not contain Cys-42 (Δ53) were both constitutively activated by H2O2. In contrast, oxidation of PKG Iα C117S maintained its cGMP-dependent activation characteristics, although oxidized PKG Iα C195S did not. To corroborate these results, we also tested the effects of our constructs on the PKG Iα–specific substrate, the large conductance potassium channel (KCa 1.1). Application of WT PKG Iα activated by either cGMP or H2O2 increased the open probabilities of the channel. Neither cGMP nor H2O2 activation of PKG Iα C42S significantly increased channel open probabilities. Moreover, cGMP-stimulated PKG Iα C117S increased KCa 1.1 activity, but this effect was not observed under oxidizing conditions. Finally, we observed that PKG Iα C42S caused channel flickers, indicating dramatically altered KCa 1.1 channel characteristics compared with channels exposed to WT PKG Iα. Cumulatively, these results indicate that constitutive activation of PKG Iα proceeds through oxidation of Cys-117 and further suggest that the formation of a sulfur acid is necessary for this phenotype.

scholarly journals The Commonly Used cGMP-dependent Protein Kinase Type I (cGKI) Inhibitor Rp-8-Br-PET-cGMPS Can Activate cGKIin Vitroand in Intact Cells

2008 ◽  
Vol 284 (1) ◽  
pp. 556-562 ◽  
Author(s):  
Nadejda Valtcheva ◽  
Peter Nestorov ◽  
Alexander Beck ◽  
Michael Russwurm ◽  
Matthias Hillenbrand ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Type I ◽  
Dependent Protein Kinase ◽  
Intact Cells ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

Physiological concentration of atrial natriuretic peptide induces endothelial regeneration in vitro

2003 ◽  
Vol 284 (4) ◽  
pp. H1388-H1397 ◽  
Author(s):  
Hyun Kook ◽  
Hiroshi Itoh ◽  
Bong Seok Choi ◽  
Naoki Sawada ◽  
Kentaro Doi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Protein Kinase ◽  
Dependent Protein Kinase ◽  
Physiological Concentration ◽  
Cell Numbers ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Regeneration In Vitro

Both nitric oxide (NO) and natriuretic peptides produce apoptosis of vascular smooth muscle cells. However, there is evidence that NO induces endothelial cell proliferation, which suggests that there is a difference in the response of endothelial cells to natriuretic peptides. The purpose of this study was to investigate the effect of atrial natriuretic peptide (ANP) on human endothelial cell survival. ANP within the physiological concentration (10−11mol/l) induced a 52% increase in the number of human coronary arterial endothelial cells and a 63% increase in human umbilical vein endothelial cells at a low concentration of serum. The increase in cell numbers was blocked by pretreatment with RP8-CPT-cGMP (RP8), a cGMP-dependent protein kinase inhibitor, with wortmannin, an Akt/PKB inhibitor, and with PD-98059, an ERK1/2 inhibitor. In a Transwell migration test, ANP also increased the cell migration, and RP8, wortmannin, and PD-98059 blocked this increase. A wound healing assay was performed to examine the effects of ANP on regeneration in vitro. ANP increased both cell numbers and migration, but the effects were blocked by the above three kinase inhibitors. ANP increased the expression of phospho-Akt and of phospho-ERK1/2 within 1.5 h. These results suggest that ANP can potentiate endothelial regeneration by cGMP-dependent protein kinase stimulation and subsequent Akt and ERK1/2 activations.

scholarly journals cGMP-Dependent Protein Kinase Type I Is Implicated in the Regulation of the Timing and Quality of Sleep and Wakefulness

PLoS ONE ◽  
2009 ◽  
Vol 4 (1) ◽  
pp. e4238 ◽  
Author(s):  
Sonja Langmesser ◽  
Paul Franken ◽  
Susanne Feil ◽  
Yann Emmenegger ◽  
Urs Albrecht ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Type I ◽  
Quality Of Sleep ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

scholarly journals Impairment of LTD and cerebellar learning by Purkinje cell–specific ablation of cGMP-dependent protein kinase I

2003 ◽  
Vol 163 (2) ◽  
pp. 295-302 ◽  
Author(s):  
Robert Feil ◽  
Jana Hartmann ◽  
Chongde Luo ◽  
Wiebke Wolfsgruber ◽  
Karl Schilling ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Motor Learning ◽  
Motor Coordination ◽  
Conditional Knockout ◽  
Type I ◽  
High Concentration ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Cerebellar Learning

The molecular basis for cerebellar plasticity and motor learning remains controversial. Cerebellar Purkinje cells (PCs) contain a high concentration of cGMP-dependent protein kinase type I (cGKI). To investigate the function of cGKI in long-term depression (LTD) and cerebellar learning, we have generated conditional knockout mice lacking cGKI selectively in PCs. These cGKI mutants had a normal cerebellar morphology and intact synaptic calcium signaling, but strongly reduced LTD. Interestingly, no defects in general behavior and motor performance could be detected in the LTD-deficient mice, but the mutants exhibited an impaired adaptation of the vestibulo-ocular reflex (VOR). These results indicate that cGKI in PCs is dispensable for general motor coordination, but that it is required for cerebellar LTD and specific forms of motor learning, namely the adaptation of the VOR.

scholarly journals Hydrogen Peroxide Enhances Vasodilatation by Increasing Dimerization of cGMP-Dependent Protein Kinase Type Iα

2012 ◽  
Vol 76 (7) ◽  
pp. 1792-1798 ◽  
Author(s):  
Dou Dou ◽  
Xiaoxu Zheng ◽  
Juan Liu ◽  
Xiaojian Xu ◽  
Liping Ye ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Protein Kinase ◽  
Type I ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

scholarly journals Increasing cGMP-dependent protein kinase I activity attenuates cisplatin-induced kidney injury through protection of mitochondria function

2013 ◽  
Vol 305 (6) ◽  
pp. F881-F890 ◽  
Author(s):  
Hasiyeti Maimaitiyiming ◽  
Yanzhang Li ◽  
Wenpeng Cui ◽  
Xiaopeng Tong ◽  
Heather Norman ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tubular Damage ◽  
Dependent Protein Kinase ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Renal Tubular

Cisplatin is widely used to treat malignancies. However, its major limitation is the development of dose-dependent nephrotoxicity. The precise mechanisms of cisplatin-induced kidney damage remain unclear, and the renoprotective agents during cisplatin treatment are still lacking. Here, we demonstrated that the expression and activity of cGMP-dependent protein kinase-I (PKG-I) were reduced in cisplatin-treated renal tubular cells in vitro as well as in the kidney tissues from cisplatin-treated mice in vivo. Increasing PKG activity by both pharmacological and genetic approaches attenuated cisplatin-induced kidney cell apoptosis in vitro. This was accompanied by decreased Bax/Bcl2 ratio, caspase 3 activity, and cytochrome c release. Cisplatin-induced mitochondria membrane potential loss in the tubular cells was also prevented by increased PKG activity. All of these data suggest a protective effect of PKG on mitochondria function in renal tubular cells. Importantly, increasing PKG activity pharmacologically or genetically diminished cisplatin-induced tubular damage and preserved renal function during cisplatin treatment in vivo. Mitochondria structural and functional damage in the kidney from cisplatin-treated mice was inhibited by increased PKG activity. In addition, increasing PKG activity enhanced ciaplatin-induced cell death in several cancer cell lines. Taken together, these results suggest that increasing PKG activity may be a novel option for renoprotection during cisplatin-based chemotherapy.

The Human Type I cGMP-Dependent Protein Kinase Gene

1991 ◽  
pp. 301-308 ◽  
Author(s):  
M. Sandberg ◽  
V. Natarajan ◽  
S. Ørstavik ◽  
S. M. Lohmann ◽  
T. Jahnsen
Keyword(s):  
Protein Kinase ◽  
Type I ◽  
Dependent Protein Kinase ◽  
Kinase Gene ◽  
Human Type ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Protein Kinase Gene
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