17β-Estradiol inhibits soluble guanylate cyclase activity through a protein tyrosine phosphatase in PC12 cells

Chen, Zi‐Jiang; Che, Danian; Vetter, Michael; Liu, Shiguo; Chang, Chung-Ho

doi:10.1016/s0960-0760(01)00122-4

Cited by 18 publications

(23 citation statements)

References 27 publications

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“…PTP inhibition changes sGC activity in two ways: the basal activity increases more than 2-fold, whereas the sensitivity toward NO decreases, and the corresponding EC 50 value more than doubles, with potentially important consequences for cellular homeostasis and activity. The findings presented herein appear to match with previous observations that overexpression of SHP-1, a cytosolic PTP, inhibited basal guanylyl cyclase activity by 56% (25). However, our finding that mutant ␤ 1 [Y192F] displays the same enzyme kinetics as WT ␤ 1 clearly suggests that Tyr phosphorylation, e.g.…”

Section: Discussionsupporting

confidence: 91%

“…For instance some reports have documented the phosphorylation of sGC on Ser/Thr residues (19 -24). Also, Tyr phosphorylation has been implicated in sGC regulation (25); however, the molecular details underlying these processes and the biological consequences of sGC phosphorylation are still obscure.…”

Section: Discussionmentioning

confidence: 99%

“…In PC12 cells Ser/Thr phosphorylation by Ca 2ϩ -dependent protein kinase enhanced sGC activity (21,22), whereas cGMPdependent protein kinase attenuated the catalytic capacity of sGC, most likely through an inhibitory feedback mechanism (23) via stimulation of protein phosphatase(s) which reduces the Ser/Thr phosphorylation level of ␤ 1 (24). Circumstantial evidence suggests that tyrosine phosphorylation may also contribute to sGC activity regulation in PC12 cells through 17␤-estradiol-mediated activation of protein tyrosine phosphatases (PTPs) such as SHP-1 (25); however, Tyr phosphorylation of sGC has not been demonstrated to date.…”

mentioning

confidence: 99%

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Reactive Oxygen Species Induce Tyrosine Phosphorylation of and Src Kinase Recruitment to NO-sensitive Guanylyl Cyclase

Meurer¹,

Pioch²,

Gross

et al. 2005

Journal of Biological Chemistry

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Soluble guanylyl cyclase (sGC) is the major cytosolic receptor for nitric oxide (NO) that converts GTP into the second messenger cGMP in a NO-dependent manner. Other factors controlling this key enzyme are intracellular proteins such as Hsp90 and PSD95, which bind to sGC and modulate its activity, stability, and localization. To date little is known about the effects of posttranslational modifications of sGC, although circumstantial evidence suggests that reversible phosphorylation may contribute to sGC regulation. Here we demonstrate that inhibitors of protein-tyrosine phosphatases such as pervanadate and bisperoxo(1,10-phenanthroline)oxovanadate(V) as well as reactive oxygen species such as H 2 O 2 induce specific tyrosine phosphorylation of the ␤ 1 but not of the ␣ 1 subunit of sGC. Tyrosine phosphorylation of sGC␤ 1 is also inducible by pervanadate and H 2 O 2 in intact PC12 cells, rat aortic smooth muscle cells, and in rat aortic tissues, indicating that tyrosine phosphorylation of sGC may also occur in vivo. We have mapped the major tyrosine phosphorylation site to position 192 of ␤ 1 , where it forms part of a highly acidic phospho-acceptor site for Src-like kinases. In the phosphorylated state Tyr(P)-192 exposes a docking site for SH2 domains and efficiently recruits Src and Fyn to sGC␤ 1 , thereby promoting multiple phosphorylation of the enzyme. Our results demonstrate that sGC is subject to tyrosine phosphorylation and interaction with Src-like kinases, revealing an unexpected cross-talk between the NO/cGMP and tyrosine kinase signaling pathways at the level of sGC.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Reactive Oxygen Species Induce Tyrosine Phosphorylation of and Src Kinase Recruitment to NO-sensitive Guanylyl Cyclase

Meurer¹,

Pioch²,

Gross

et al. 2005

Journal of Biological Chemistry

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“…The results presented in this study suggest an alternate mechanism through which contractile agonists can decrease cGMP levels by inhibitory phosphorylation of sGC, and this mechanism would probably be exploited by any stimulus that leads to Src activation. Our results are consistent with the studies of Meurer et al (2005) demonstrating that inhibitors of protein tyrosine phosphatases and reactive oxygen species such as H 2 O 2 induced tyrosine phosphorylation of sGC ␤1 subunit at Tyr192 in PC12 cells, rat aortic smooth muscle cells, and aortic tissue, but in variance with the studies of Chen et al (2001) demonstrating that overexpression of the protein tyrosine phosphatase Src homology phosphatase-1 inhibited basal and sodium nitroprusside-stimulated cGMP formation. Although not studied, identification of the specific Src kinase that phosphorylate sGC should provide some insight into which agonist might regulate sGC activity and what other physiological processes might be affected.…”

Section: Discussionsupporting

confidence: 92%

Inhibitory Phosphorylation of Soluble Guanylyl Cyclase by Muscarinic m2 Receptors via Gβγ-Dependent Activation of c-Src Kinase

Murthy

2008

J Pharmacol Exp Ther

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In gastrointestinal smooth muscle, cGMP levels in response to relaxant agonists are regulated by activation of phosphodiesterase 5 and inhibition of soluble guanylyl cyclase (sGC) in a feedback mechanism via cGMP-dependent protein kinase. The aim of the present study was to determine whether contractile agonists modulate cGMP levels by cross-regulating sGC activity. In gastric muscle cells, acetylcholine (ACh) stimulated Src activity and induced sGC phosphorylation. Concurrent stimulation of cells with ACh attenuated sGC activity and cGMP formation in response to the nitric oxide (NO) donor, S-nitrosoglutathione (GSNO). The effect of ACh on Src activity, sGC phosphorylation, and on GSNO-stimulated sGC activity and cGMP formation were blocked by the m2 receptor antagonist (methoctramine), pertussis toxin, and by inhibitors of phosphatidylinositol 3 kinase, LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride], or Src kinase, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4-d]pyrimidine, in dispersed muscle cells and in cells expressing G␣ i minigene or G␤␥-scavenging peptide, whereas the m3 receptor antagonist, N-(2-chloroethyl)-4-piperidinyl diphenylacetate, or expression of the G␣ q minigene had no effect. ACh also attenuated sGC activity and cGMP formation in response to the NOindependent activator, YC-1 [3-(5Ј-hydroxymethyl-2Јfuryl)-1-benzylindazole]. The pattern implied that phosphorylation of sGC by c-Src kinase inhibits NO-sensitive sGC activity, and the inhibition was not due to a decrease in the binding of NO but probably due to decrease in catalytic activity. We conclude that cGMP levels are cross-regulated by contractile agonists via a mechanism that involves c-Src-dependent phosphorylation of sGC, leading to inhibition of sGC activity and cGMP formation. The finding highlights a novel mechanism for attenuation of the NO/sGC/cGMP signal by G i -coupled contractile agonists, in addition to their inhibitory effect on adenylyl cyclase and cAMP formation.In the gastrointestinal smooth muscle, the relaxant neurotransmitters vasoactive intestinal peptide (VIP) and pituitary adenylyl cycle-activating peptide, which are colocalized with nitric oxide (NO) synthase, are coreleased with NO in response to neural activation resulting in the generation of cAMP and cGMP and activation of both cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) (Kunze and Furness, 1999;Bornstein et al., 2004;Murthy, 2006). The levels of cAMP and cGMP are determined by the activities of cyclases and phosphodiesterases.

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“…These E 2 effects were only observed after in vivo treatment, and it has been suggested that they are indirect. In addition, it has been reported that E 2 affects sGC expression and activity in uterus, PC12 cells, and hypothalamus (8,10,14). Previous studies from our laboratory (4) show that acute E 2 treatment exerts an inhibitory effect on sGC by downregulating the sGC␤ 1 subunit and sGC activity but increases sGC␣ 1 expression in anterior pituitary gland from immature rats.…”

mentioning

confidence: 84%

Nitric oxide sensitive-guanylyl cyclase subunit expression changes during estrous cycle in anterior pituitary glands

Cabilla¹,

Ronchetti²,

Nudler³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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Cabilla JP, Ronchetti SA, Nudler SI, Miler EA, Quinteros FA, Duvilanski BH. Nitric oxide sensitive-guanylyl cyclase subunit expression changes during estrous cycle in anterior pituitary glands. Am J Physiol Endocrinol Metab 296: E731-E737, 2009. First published January 13, 2009 doi:10.1152/ajpendo.90795.2008.-17␤-Estradiol (E 2 ) exerts inhibitory actions on the nitric oxide pathway in rat adult pituitary glands. Previously, we reported that in vivo E 2 acute treatment had opposite effects on soluble guanylyl cyclase (sGC) subunits, increasing ␣ 1-and decreasing ␤1-subunit protein and mRNA expression and decreasing sGC activity in immature rats. Here we studied the E 2 effect on sGC protein and mRNA expression in anterior pituitary gland from adult female rats to address whether the maturation of the hypothalamus-pituitary axis influences its effects and to corroborate whether these effects occur in physiological conditions such as during estrous cycle. E 2 administration causes the same effect on sGC as seen in immature rats, and these effects are estrogen receptor dependent. These results suggest that E 2 is the main effector of these changes. Since the sGC ␣-subunit increases while the sGC activity decreases, we studied if other less active isoforms of the sGC ␣-subunit are expressed. Here we show for the first time that sGC␣ 2 and sGC␣2 inhibitory (␣2i) isoforms are expressed in this gland, but only sGC␣ 2i mRNA increased after E2 acute treatment. Finally, to test whether E 2 effects take place under a physiological condition, sGC subunit expression was monitored over estrous cycle. sGC␣ 1, -␤1, and -␣ 2i fluctuate along estrous cycle, and these changes are directly related with E2 level fluctuations rather than to NO level variations. These findings show that E2 physiologically regulates sGC expression and highlight a novel mechanism by which E2 downregulates sGC activity in rat anterior pituitary gland. estrogen; soluble guanylyl cyclase; inhibitory subunit THE MAIN ESTROGENIC HORMONE 17␤-estradiol (E 2 ) plays important regulatory roles in a broad variety of biological processes, acting mainly on reproductive tissues, bone, liver, pituitary, and brain (9, 25).Nitric oxide (NO) is a signaling molecule that freely diffuses across cellular membranes where it binds to its main intracellular receptor, soluble guanylyl cyclase (sGC). This enzyme catalyzes the formation of cGMP from GTP. Subsequently, targets of cGMP such as cGMP-dependent protein kinases, cyclic nucleotide phosphodiesterases, and cyclic nucleotidesensitive ion channels are activated to continue the signal transduction (15,18).sGC is an heterodimeric enzyme and is comprised of two subunits, ␣ and ␤, of which four types exist (␣ 1 , ␣ 2, ␤ 1 , and ␤ 2 ). Both ␣-isoforms form a functional enzyme with the ␤ 1 -subunit, although the ␣ 1 ␤ 1 is the most abundant and widely expressed heterodimer, showing the greater activity (12, 13). The ␣ 2 is expressed in a more restricted pattern: in human tissues, it is present mainly in spleen, placenta, brain, ...

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17β-Estradiol inhibits soluble guanylate cyclase activity through a protein tyrosine phosphatase in PC12 cells

Cited by 18 publications

References 27 publications

Reactive Oxygen Species Induce Tyrosine Phosphorylation of and Src Kinase Recruitment to NO-sensitive Guanylyl Cyclase

Reactive Oxygen Species Induce Tyrosine Phosphorylation of and Src Kinase Recruitment to NO-sensitive Guanylyl Cyclase

Inhibitory Phosphorylation of Soluble Guanylyl Cyclase by Muscarinic m2 Receptors via Gβγ-Dependent Activation of c-Src Kinase

Nitric oxide sensitive-guanylyl cyclase subunit expression changes during estrous cycle in anterior pituitary glands

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