Hydrogen sulfide stimulates CFTR in Xenopus oocytes by activation of the cAMP/PKA signalling axis

Perniss, Alexander; Preiss, Kathrin; Nier, Marcel; Althaus, Mike

doi:10.1038/s41598-017-03742-5

Cited by 14 publications

(11 citation statements)

References 56 publications

(80 reference statements)

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“…In addition, an increase in the intracellular cAMP concentration could result from the inhibition of cAMP degradation by PDE. Thus, H 2 S may stimulate AC or inhibit PDE; both would result in accumulation of intracellular cAMP (28). Indeed, GYY4137 potentiated the effect of forskolin on AQP-2 expression in the current study.…”

Section: Discussionmentioning

confidence: 44%

Hydrogen sulfide upregulates renal AQP‐2 protein expression and promotes urine concentration

Luo

Liu

et al. 2018

The FASEB Journal

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Increasing evidence supports the important role of HS in renal physiology and the pathogenesis of kidney injury. Whether HS regulates water metabolism in the kidney and the potential mechanism are still unknown. The present study was conducted to determine the role of HS in urine concentration. Inhibition of both cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS), 2 major enzymes for endogenous HS production, with propargylglycine (PPG) and amino-oxyacetate (AOAA), respectively, caused increased urine output and reduced urine osmolality in mice that was associated with decreased expression of aquaporin (AQP)-2 in the renal inner medulla. Mice treated with both PPG and AOAA developed a urine concentration defect in response to dehydration that was accompanied by reduced AQP-2 protein expression. Inhibition of CSE alone was associated with a mild decrease in AQP-2 protein level in the renal medulla of heterozygous CBS mice. GYY4137, a slow HS donor, markedly improved urine concentration and prevented the down-regulation of renal AQP-2 protein expression in mice with lithium-induced nephrogenic diabetes insipidus (NDI). GYY4137 significantly increased cAMP levels in cell lysates prepared from inner medullary collecting duct (IMCD) suspensions. AQP-2 protein expression was also upregulated, but was significantly inhibited by the adenyl cyclase inhibitor MDL12330A or the PKA inhibitor H89, but not the vasopressin 2 receptor (VR) antagonist tolvaptan. Inhibition of endogenous HS production impaired urine concentration in mice, whereas an exogenous HS donor improved urine concentration in lithium-induced NDI by increasing AQP-2 expression in the collecting duct principal cells. HS upregulated AQP-2 protein expression, probably via the cAMP-PKA pathway.-Luo, R., Hu, S., Liu, Q., Han, M., Wang, F., Qiu, M., Li, S., Li, X., Yang, T., Fu, X., Wang, W., Li, C. Hydrogen sulfide upregulates renal AQP-2 protein expression and promotes urine concentration.

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Section: Discussionmentioning

confidence: 44%

Hydrogen sulfide upregulates renal AQP‐2 protein expression and promotes urine concentration

Luo

Liu

et al. 2018

The FASEB Journal

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“…In case of newborn animals we still observed the decrease of NMDA-evoked currents after application of NaHS, which indicates on PKA-independent mode of H 2 S action on GluN1/2B NMDA receptors. Moreover the effects of H 2 S on cAMP production are varied among different cell types or tissues and may be secondary to other signaling pathways (e.g., COX-2 or phosphodiesterase; Njie-Mbye et al, 2012 ; Perniss et al, 2017 ). Whereas the study of Kimura ( 2000 ) provides evidence for an activation of the cAMP-pathway by H 2 S, inhibition of cAMP-concentration has also been reported (Yong et al, 2008 ; Nagpure and Bian, 2014 ; Yang et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Age-Dependent, Subunit Specific Action of Hydrogen Sulfide on GluN1/2A and GluN1/2B NMDA Receptors

Yakovlev

Kurmasheva

Ishchenko

et al. 2017

Front. Cell. Neurosci.

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Hydrogen sulfide (H2S) is an endogenously produced neuroactive gas implicated in many key processes in the peripheral and central nervous system. Whereas the neuroprotective role of H2S has been shown in adult brain, the action of this messenger in newborns remains unclear. One of the known targets of H2S in the nervous system is the N-methyl-D-aspartate (NMDA) glutamate receptor which can be composed of different subunits with distinct functional properties. In the present study, using patch clamp technique, we compared the effects of the H2S donor sodium hydrosulfide (NaHS, 100 μM) on hippocampal NMDA receptor mediated currents in rats of the first and third postnatal weeks. This was supplemented by testing effects of NaHS on recombinant GluN1/2A and GluN1/2B NMDA receptors expressed in HEK293T cells. The main finding is that NaHS action on NMDA currents is age-dependent. Currents were reduced in newborns but increased in older juvenile rats. Consistent with an age-dependent switch in NMDA receptor composition, in HEK239T cells expressing GluN1/2A receptors, NaHS increased NMDA activated currents associated with acceleration of desensitization and decrease of the deactivation rate. In contrast, in GluN1/2B NMDA receptors, which are prevalent in newborns, NaHS decreased currents and reduced receptor deactivation without effect on the desensitization rate. Adenylate cyclase inhibitor MDL-12330A (10 μM) did not prevent the age-dependent effects of NaHS on NMDA evoked currents in pyramidal neurons of hippocampus. The reducing agent dithiothreitol (DTT, 2 mM) applied on HEK293T cells prevented facilitation induced by NaHS on GluN1/2A NMDA receptors, however in GluN1/2B NMDA receptors the inhibitory effect of NaHS was still observed. Our data indicate age-dependent effect of H2S on NMDA receptor mediated currents determined by glutamate receptor subunit composition. While the inhibitory action of H2 on GluN1/2B receptors could limit the excessive activation in early age, the enhanced functionality of GluN1/2A receptor in the presence of this gasotransmitter can enlarge synaptic efficacy and promote synaptic plasticity in adults.

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“…The R751L-CFTR mutation was generated by site-directed mutagenesis using the QuikChangeLightning Kit (Agilent Technologies, Cheshire, UK) according to the manufacturer's instructions and using the forward (5 0 -ctgatcacgctgatgagaggcagtatcgcct-3 0 ) and reverse primer (5 0 -aggcgatactgcctctcatcagcgtgatcag-3 0 ) sequences. Successful mutation generation was verified by DNA sequencing and cRNA synthesized as previously described (17) Oocytes were placed in a Lucite chamber and continuously perfused with oocyte Ringer's solution (in mM: 90 NaCl, 1 KCl, 2 CaCl 2 , and 5 HEPES, pH 7.4). Microelectrode recordings were performed as previously described (17).…”

Section: Synthesis Of Crna and Heterologous Expression In Xenopus Oocmentioning

confidence: 99%

Clinical and molecular characterization of the R751L-CFTR mutation

Haq

Althaus

Gardner

et al. 2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cystic fibrosis (CF) arises from mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in progressive and life-limiting respiratory disease. R751L is a rare CFTR mutation that is poorly characterised. Our aims were to describe the clinical and molecular phenotypes associated with R751L. Relevant clinical data were collected from three heterozygote individuals harbouring R751L (2 patients with G551D/R751L and 1 with F508del/R751L). Assessment of R751L-CFTR function was made in primary human bronchial epithelial cultures (HBEs) and Xenopus oocytes. Molecular properties of R751L-CFTR were investigated in the presence of known CFTR modulators. Although sweat chloride was elevated in all three patients, the clinical phenotype associated with R751L was mild. Chloride secretion in F508del/R751L HBEs was reduced compared to non-CF HBEs and associated with a reduction in sodium absorption by the epithelial sodium channel (ENaC). However, R751L-CFTR function in Xenopus oocytes together with folding and cell surface transport of R751L-CFTR were not different to wild-type CFTR. Overall, R751L-CFTR was associated with reduced sodium chloride absorption but had similar functional properties to wild-type CFTR. This is the first report of R751L-CFTR that combines clinical phenotype with characterisation of functional and biological properties of the mutant channel. Our work will build upon existing knowledge of mutations within this region of CFTR and importantly inform approaches for clinical management. Elevated sweat chloride and reduced chloride secretion in HBEs may be due to alternative non-CFTR factors, which require further investigation.

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Hydrogen sulfide stimulates CFTR in Xenopus oocytes by activation of the cAMP/PKA signalling axis

Cited by 14 publications

References 56 publications

Hydrogen sulfide upregulates renal AQP‐2 protein expression and promotes urine concentration

Hydrogen sulfide upregulates renal AQP‐2 protein expression and promotes urine concentration

Age-Dependent, Subunit Specific Action of Hydrogen Sulfide on GluN1/2A and GluN1/2B NMDA Receptors

Clinical and molecular characterization of the R751L-CFTR mutation

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