Hydrogen Sulfide and Urogenital Tract

Bianca, Roberta d’Emmanuele di Villa; Cirino, Giuseppe; Sorrentino, Raffaella

doi:10.1007/978-3-319-18144-8_5

Cited by 17 publications

(7 citation statements)

References 97 publications

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“…The H 2 S pathway is involved in many physiological and pathological processes in different organs and apparatuses in animal experimental models and in human [ 5 – 8 ]. Recently, a role for the L-cysteine/H 2 S pathway has been proposed in human urogenital tract [ 9 – 15 ]. Within this context, we have previously demonstrated that CBS and CSE are both expressed in the human bladder and that either an H 2 S donor or L-cysteine relaxes human bladder strips.…”

Section: Introductionmentioning

confidence: 99%

Human Cystathionine-β-Synthase Phosphorylation on Serine227 Modulates Hydrogen Sulfide Production in Human Urothelium

et al. 2015

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Urothelium, the epithelial lining the inner surface of human bladder, plays a key role in bladder physiology and pathology. It responds to chemical, mechanical and thermal stimuli by releasing several factors and mediators. Recently it has been shown that hydrogen sulfide contributes to human bladder homeostasis. Hydrogen sulfide is mainly produced in human bladder by the action of cystathionine-β-synthase. Here, we demonstrate that human cystathionine-β-synthase activity is regulated in a cGMP/PKG-dependent manner through phosphorylation at serine 227. Incubation of human urothelium or T24 cell line with 8-Bromo-cyclic-guanosine monophosphate (8-Br-cGMP) but not dibutyryl-cyclic-adenosine monophosphate (d-cAMP) causes an increase in hydrogen sulfide production. This result is congruous with the finding that PKG is robustly expressed but PKA only weakly present in human urothelium as well as in T24 cells. The cGMP/PKG-dependent phosphorylation elicited by 8-Br-cGMP is selectively reverted by KT5823, a specific PKG inhibitor. Moreover, the silencing of cystathionine-β-synthase in T24 cells leads to a marked decrease in hydrogen sulfide production either in basal condition or following 8-Br-cGMP challenge. In order to identify the phosphorylation site, recombinant mutant proteins of cystathionine-β-synthase in which Ser32, Ser227 or Ser525 was mutated in Ala were generated. The Ser227Ala mutant cystathionine-β-synthase shows a notable reduction in basal biosynthesis of hydrogen sulfide becoming unresponsive to the 8-Br-cGMP challenge. A specific antibody that recognizes the phosphorylated form of cystathionine-β-synthase has been produced and validated by using T24 cells and human urothelium. In conclusion, human cystathionine-β-synthase can be phosphorylated in a PKG-dependent manner at Ser227 leading to an increased catalytic activity.

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Section: Introductionmentioning

confidence: 99%

Human Cystathionine-β-Synthase Phosphorylation on Serine227 Modulates Hydrogen Sulfide Production in Human Urothelium

et al. 2015

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“…Here, we have addressed the role of H 2 S as possible downstream mediator following activation of M receptors within the urothelium. Indeed, endogenous H 2 S is a signaling molecule which participates in the regulation of various physiological processes in human urogenital-tract 11 16 17 21 24 25 26 . The choice of the urothelium stems from the finding that CBS is markedly expressed in the urothelium as compared to CSE and that its activity is specifically enhanced upon phosphorylation 21 .…”

Section: Discussionmentioning

confidence: 99%

“…H 2 S, is the third gaseous transmitter along with nitric oxide (NO) and carbon monoxide, formed by L-cysteine mainly through the action of cysthationine-β-synthase (CBS) and cysthationine-γ-lyase (CSE) 12 13 14 15 . It is endogenously produced in urinary bladder of trout, mouse, and rat implying that the contribution of this pathway to bladder function is conserved in different species including human 16 . Moreover, animal pre-clinical studies showed that H 2 S causes smooth muscle relaxation and/or contraction depending on the species and experimental conditions used 17 18 19 20 .…”

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confidence: 99%

Urothelium muscarinic activation phosphorylates CBSSer227 via cGMP/PKG pathway causing human bladder relaxation through H2S production

Bianca

Mitidieri

Fusco³

et al. 2016

Sci Rep

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The urothelium modulates detrusor activity through releasing factors whose nature has not been clearly defined. Here we have investigated the involvement of H2S as possible mediator released downstream following muscarinic (M) activation, by using human bladder and urothelial T24 cell line. Carbachol stimulation enhances H2S production and in turn cGMP in human urothelium or in T24 cells. This effect is reversed by cysthationine-β-synthase (CBS) inhibition. The blockade of M1 and M3 receptors reverses the increase in H2S production in human urothelium. In T24 cells, the blockade of M1 receptor significantly reduces carbachol-induced H2S production. In the functional studies, the urothelium removal from human bladder strips leads to an increase in carbachol-induced contraction that is mimicked by CBS inhibition. Instead, the CSE blockade does not significantly affect carbachol-induced contraction. The increase in H2S production and in turn of cGMP is driven by CBS-cGMP/PKG-dependent phosphorylation at Ser227 following carbachol stimulation. The finding of the presence of this crosstalk between the cGMP/PKG and H2S pathway downstream to the M1/M3 receptor in the human urothelium further implies a key role for H2S in bladder physiopathology. Thus, the modulation of the H2S pathway can represent a feasible therapeutic target to develop drugs for bladder disorders.

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“…As a member of gasotransmitters, H 2 S has been identified in several tissues of male reproductive system from various mammalian species (Sugiura et al, 2005; d’Emmanuele di Villa Bianca et al, 2009; Li et al, 2011; di Villa Bianca et al, 2015). However, the existence and the functional roles of H 2 S in epididymis remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…In the male reproductive system, endogenous H 2 S-generating enzymes CBS and CSE have been identified in human penile, rat testis, and vas deferens (Sugiura et al, 2005; Li et al, 2012; di Villa Bianca et al, 2015). Similar to rat testis, our results demonstrated the distribution of these two enzymes was distinct in rat epididymal tissue.…”

Section: Discussionmentioning

confidence: 99%

Cellular Mechanism Underlying Hydrogen Sulfide Mediated Epithelial K+ Secretion in Rat Epididymis

Gao

Qin

et al. 2019

Front. Physiol.

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As a novel gasotransmitter, hydrogen sulfide (H2S) elicits various physiological actions including smooth muscle relaxation and promotion of transepithelial ion transport. However, the pro-secretory function of H2S in the male reproductive system remains largely unclear. The aim of this study is to elucidate the possible roles of H2S in modulating rat epididymal intraluminal ionic microenvironment essential for sperm storage. The results revealed that endogenous H2S-generating enzymes cystathionine β-synthetase (CBS) and cystathionine γ-lyase (CSE) were both expressed in rat epididymis. CBS located predominantly in epithelial cells whilst CSE expressed primarily in smooth muscle cells. The relative expression level of CBS and CSE escalated from caput to cauda regions of epididymis, which was paralleled to the progressively increasing production of endogenous H2S. The effect of H2S on epididymal epithelial ion transportation was investigated using short-circuit current (ISC), measurement of intracellular ion concentration and in vivo rat epididymal microperfusion. Our data showed that H2S induced transepithelial K+ secretion via adenosine triphosphate-sensitive K+ (KATP) channel and large conductance Ca2+-activated K+ (BKCa) channel. Transient receptor potential vanilloid 4 (TRPV4) channel-mediated Ca2+ influx was implicated in the activation of BKCa channel. In vivo studies further demonstrated that H2S promoted K+ secretion in rat epididymal epithelium. Inhibition of endogenous H2S synthesis caused a significant decrease in K+ concentration of cauda epididymal intraluminal fluid. Moreover, our data demonstrated that high extracellular K+ concentration actively depressed the motility of cauda epididymal sperm in a pH-independent manner. Collectively, the present study demonstrated that H2S was vital to the formation of high K+ concentration in epididymal intraluminal fluid by promoting the transepithelial K+ secretion, which might contribute to the maintenance of the cauda epididymal sperm in quiescent dormant state before ejaculation.

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Hydrogen Sulfide and Urogenital Tract

Cited by 17 publications

References 97 publications

Human Cystathionine-β-Synthase Phosphorylation on Serine227 Modulates Hydrogen Sulfide Production in Human Urothelium

Human Cystathionine-β-Synthase Phosphorylation on Serine227 Modulates Hydrogen Sulfide Production in Human Urothelium

Urothelium muscarinic activation phosphorylates CBSSer227 via cGMP/PKG pathway causing human bladder relaxation through H2S production

Cellular Mechanism Underlying Hydrogen Sulfide Mediated Epithelial K+ Secretion in Rat Epididymis

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