scholarly journals Protein Kinase G Phosphorylates Soluble Guanylyl Cyclase on Serine 64 and Inhibits Its Activity

2008 ◽  
Vol 28 (10) ◽  
pp. 1803-1810 ◽  
Author(s):  
Zongmin Zhou ◽  
Nazish Sayed ◽  
Anastasia Pyriochou ◽  
Charis Roussos ◽  
David Fulton ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Protein Kinase G

Abstract 556: The Soluble Guanylyl Cyclase Activator Bay 60-2770 Inhibits Arterial Smooth Muscle Cell Migration in Protein Kinase G-dependent Manner

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Andrew Holt ◽  
Danielle Martin ◽  
Patti Shaver ◽  
Shaquria Adderley ◽  
Joshua Stone ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cell Migration ◽  
Protein Kinase ◽  
Cyclic Gmp ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Protein Kinase G ◽  
Growth Disorders ◽  
Arterial Smooth Muscle ◽  
Cyclase Activator

Atherosclerotic lower extremity peripheral artery disease (PAD) is among the most prevalent, morbid and mortal of all cardiovascular disorders. Pathologic arterial smooth muscle (ASM) cell migration is a major component of atherogenic PAD and efforts aimed at attenuating its progression are clinically essential. Cyclic nucleotide signaling has long been studied for its growth-mitigating properties in the setting of PAD and other vascular growth disorders. In this study we hypothesized that the novel, heme-independent soluble guanylyl cyclase activator BAY 60-2770 (BAY) inhibits ASM cell migration through phosphorylation of the protein kinase G (PKG) target and actin-binding protein vasodilator-stimulated phosphoprotein (VASP). In a rat model of injury-induced arterial growth, BAY significantly reduced neointima formation and luminal narrowing compared to vehicle (Veh)-treated control arteries after 2 weeks. Using rat and human ASM cells BAY significantly attenuated cell migration, reduced G:F actin, and increased cyclic GMP content, PKG activity and phosphorylated VASP at Ser239 (pVASP.S239) compared to Veh controls. Using site-directed mutagenesis, both full-length VASP-overexpressing (wild type, WT) and VASP.S239 phosphorylation-resistant mutants showed significantly reduced cell migration compared to naïve controls, however, there was no effect on cell migration between either VASP transfected group in the presence of BAY. Interestingly, both VASP mutants showed significantly increased PKG activity compared to naïve cells, and in turn pharmacologic PKG blockade in the presence of BAY fully reversed the inhibitory effect of BAY alone on cell migration. These data suggest BAY has capacity to inhibit ASM cell migration through cyclic GMP/PKG/VASP signaling yet through mechanisms independent of pVASP.S239. Findings from this study implicate BAY via cyclic GMP/PKG/VASP as a potential pharmacotherapeutic agent against aberrant ASM growth disorders such as PAD.

scholarly journals Protein kinase G phosphorylates soluble guanylyl cyclase and inhibits its activity

2007 ◽  
Vol 7 (S1) ◽  
Author(s):  
Andreas Papapetropoulos ◽  
Zongmin Zhou ◽  
Nazish Sayed ◽  
Anastasia Pyriochou ◽  
Charis Roussos ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Protein Kinase G

Gaseous Transmitter Regulation of Catecholamine Secretion by hypoxia in Murine Adrenal Chromaffin Cells

2021 ◽  
Author(s):  
Anna Gridina ◽  
Xiaoyu Su ◽  
Shakil A. Khan ◽  
Ying-Jie Peng ◽  
Benjamin L Wang ◽  
...  
Keyword(s):  
Nervous System ◽  
Protein Kinase ◽  
Guanylyl Cyclase ◽  
Chromaffin Cells ◽  
Soluble Guanylyl Cyclase ◽  
Protein Kinase G ◽  
Adrenal Chromaffin Cells ◽  
Wild Type ◽  
Genetic Deletion ◽  
Adrenal Chromaffin

Emerging evidence suggests that gaseous molecules, carbon monoxide (CO) and hydrogen sulfide (H2S) generated by heme oxygenase-(HO)-2 and cystathionine γ-lyase (CSE), respectively, function as transmitters in the nervous system. Present study examined the roles of CO and H2S in hypoxia-induced catecholamine (CA) release from adrenal medullary chromaffin cells (AMC). Studies were performed on AMC from adult (≥6 weeks of age) wild type (WT), HO-2 null, CSE null and HO-2/CSE double null mice of either gender. CA secretion was determined by carbon fiber amperometry and [Ca2+]i by microflurometry using Fura-2. HO-2- and CSE immunoreactivities were seen in WT AMC, which were absent in HO-2 and CSE null mice. Hypoxia (medium pO2 30-38 mmHg) evoked CA release and elevated [Ca2+]i. The magnitude of hypoxic response was greater in HO-2 null mice and in HO inhibitor treated WT AMC compared to controls. H2S levels were elevated in HO-2 null AMC. Either pharmacological inhibition or genetic deletion of CSE prevented the augmented hypoxic responses of HO-2 null AMC and H2S donor rescued AMC responses to hypoxia in HO-2/CSE double null mice. CORM-3, a CO donor, prevented the augmented hypoxic responses in WT and HO-2 null AMC. CO donor reduced H2S levels in WT AMC. The effects of CO donor were blocked by either ODQ or 8pCT, inhibitors of soluble guanylyl cyclase (SGC) or protein kinase G, respectively. These results suggest that HO-2-derived CO inhibits hypoxia-evoked CA secretion from adult murine AMC involving soluble guanylyl cyclase (SGC)-protein kinase G (PKG)-dependent regulation of CSE- derived H2S.

Protein kinase G is not essential to NO-cGMP modulation of basal tone in rat pulmonary circulation

1998 ◽  
Vol 274 (2) ◽  
pp. H672-H678 ◽  
Author(s):  
Brian Fouty ◽  
Padmini Komalavilas ◽  
Masashi Muramatsu ◽  
Alan Cohen ◽  
Ivan F. McMurtry ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Guanylyl Cyclase ◽  
Pulmonary Circulation ◽  
Vascular Tone ◽  
Perfusion Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Soluble Guanylyl Cyclase ◽  
Physiological Effect ◽  
Protein Kinase G ◽  
Similar Degree

Nitric oxide (NO) is important in modulating increased pulmonary vascular tone. Whereas in other systems it is believed that the action of NO is mediated through guanosine 3′,5′-cyclic monophosphate (cGMP) and protein kinase G (PKG), the validity of this pathway in the pulmonary circulation has not been established. Using isolated salt-perfused normotensive and hypertensive rat lungs, we studied the effects of the soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and the PKG inhibitors, KT5823, Rp-8-pCPT-cGMPS, and { N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide} (H-8), on pulmonary vascular resistance. In isolated normotensive lungs, ODQ-mediated inhibition of soluble guanylyl cyclase augmented hypoxic pulmonary vasoconstriction, whereas the PKG inhibitors had no effect. Despite the marked differences in the physiological effect, ODQ and Rp-8-pCPT-cGMPS inhibited PKG activity to a similar degree as determined by a back-phosphorylation assay showing decreased PKG-mediated phosphorylation of serine 1755 on thed- myo-inositol 1,4,5-trisphosphate receptor. In hypertensive lungs, inhibition of soluble guanylyl cyclase by ODQ increased perfusion pressure by 101 ± 20% ( P < 0.05), an increase similar to that seen with inhibition of NO synthase (NOS), confirming an essential role for cGMP. In contrast, KT5823, Rp-8-pCPT-cGMPS, and H-8 (used in doses 5- to 100-fold in excess of their reported inhibitory concentrations for PKG) caused only a small increase in baseline perfusion pressure (14 ± 2%, P = not significant from vehicle control). Effectiveness of PKG inhibition in the hypertensive lungs was also confirmed with the back-phosphorylation assay. These studies suggest that whereas NO-mediated modulation of vascular tone in the normotensive and hypertensive pulmonary circulation is dependent on cGMP formation, activation of PKG may not be essential.

scholarly journals Alteration of Basilar Artery Rho-Kinase and Soluble Guanylyl Cyclase Protein Expression in a Rat Model of Cerebral Vasospasm following Subarachnoid Hemorrhage

2014 ◽  
Vol 2014 ◽  
pp. 1-8
Author(s):  
Chih-Jen Wang ◽  
Pei-Yu Lee ◽  
Bin-Nan Wu ◽  
Shu-Chuan Wu ◽  
Joon-Khim Loh ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Protein Kinase ◽  
Protein Expression ◽  
Cerebral Vasospasm ◽  
Basilar Artery ◽  
Guanylyl Cyclase ◽  
Autologous Blood ◽  
Rho Kinase ◽  
Soluble Guanylyl Cyclase ◽  
Western Blots

Background and Purpose. The vasoconstrictor endothelin-1 (ET-1) has been implicated in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). Previous results showed that CGS 26303, an endothelin converting enzyme (ECE) inhibitor, effectively prevented and reversed arterial narrowing in animal models of SAH. In the present study, we assessed the effect of CGS 26303 on neurological deficits in SAH rats. The involvement of vasoactive pathways downstream of ET-1 signaling in SAH was also investigated.Methods. Sprague-Dawley rats were divided into five groups (n=6/group): (1) normal control, (2) SAH, (3) SAH+vehicle, (4) SAH+CGS 26303 (prevention), and (5) SAH+CGS 26303 (reversal). SAH was induced by injecting autologous blood into cisterna magna. CGS 26303 (10 mg/kg) was injected intravenously at 1 and 24 hr after the initiation of SAH in the prevention and reversal protocols, respectively. Behavioral changes were assessed at 48 hr after SAH. Protein expression was analyzed by Western blots.Results. Deficits in motor function were obvious in the SAH rats, and CGS 26303 significantly improved the rate of paraplegia. Expressions of rho-kinase-II and membrane-bound protein kinase C-δand rhoA were significantly increased, while those of soluble guanylyl cyclaseα1andβ1as well as protein kinase G were significantly decreased in the basilar artery of SAH rats. Treatment with CGS 26303 nearly normalized these effects.Conclusions. These results demonstrate that the rhoA/rho-kinase and sGC/cGMP/PKG pathways play pivotal roles in cerebral vasospasm after SAH. It also shows that ECE inhibition is an effective strategy for the treatment of this disease.

scholarly journals Dependence of Electrical Activity and Calcium Influx-Controlled Prolactin Release on Adenylyl Cyclase Signaling Pathway in Pituitary Lactotrophs

2006 ◽  
Vol 20 (9) ◽  
pp. 2231-2246 ◽  
Author(s):  
Arturo E. Gonzalez-Iglesias ◽  
Yonghua Jiang ◽  
Melanija Tomić ◽  
Karla Kretschmannova ◽  
Silvana A. Andric ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Adenylyl Cyclase ◽  
Guanylyl Cyclase ◽  
Cyclic Nucleotide ◽  
Action Potentials ◽  
Soluble Guanylyl Cyclase ◽  
Cgmp Production ◽  
Camp And Cgmp ◽  
Kinase A

Abstract Pituitary lactotrophs in vitro fire extracellular Ca2+-dependent action potentials spontaneously through still unidentified pacemaking channels, and the associated voltage-gated Ca2+ influx (VGCI) is sufficient to maintain basal prolactin (PRL) secretion high and steady. Numerous plasma membrane channels have been characterized in these cells, but the mechanism underlying their pacemaking activity is still not known. Here we studied the relevance of cyclic nucleotide signaling pathways in control of pacemaking, VGCI, and PRL release. In mixed anterior pituitary cells, both VGCI-inhibitable and -insensitive adenylyl cyclase (AC) subtypes contributed to the basal cAMP production, and soluble guanylyl cyclase was exclusively responsible for basal cGMP production. Inhibition of basal AC activity, but not soluble guanylyl cyclase activity, reduced PRL release. In contrast, forskolin stimulated cAMP and cGMP production as well as pacemaking, VGCI, and PRL secretion. Elevation in cAMP and cGMP levels by inhibition of phosphodiesterase activity was also accompanied with increased PRL release. The AC inhibitors attenuated forskolin-stimulated cyclic nucleotide production, VGCI, and PRL release. The cell-permeable 8-bromo-cAMP stimulated firing of action potentials and PRL release and rescued hormone secretion in cells with inhibited ACs in an extracellular Ca2+-dependent manner, whereas 8-bromo-cGMP and 8-(4-chlorophenyltio)-2′-O-methyl-cAMP were ineffective. Protein kinase A inhibitors did not stop spontaneous and forskolin-stimulated pacemaking, VGCI, and PRL release. These results indicate that cAMP facilitates pacemaking, VGCI, and PRL release in lactotrophs predominantly in a protein kinase A- and Epac cAMP receptor-independent manner.

Sign in / Sign up

Export Citation Format

Share Document