regulation of breathing, H2S signalling, dopamine, serotonin - brief notes
Hydrogen sulfide (H2S) signalling is involved in the central regulation of breathing / ventilatory response. If the enzyme that makes H2S, cystathionine beta synthase, (CBS) is blocked, the neural network that controls breathing in the brain breaks down and gasping results.
https://www.nature.com/articles/s42003-020-01312-6
Dopamine and serotonin upregulate CBS activity. CBS has a heme moiety and needs vitamin B6 as a cofactor.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022568
"Cystathionine-β-synthase (CBS) is the most likely endogenous candidate enzyme to increase H2S production. Endogenous H2S is mainly synthesized by CBS and cystathionine-γ-lyase [8], [9]. Both enzymes depend on pyridoxal 5′-phosphate (PLP) as a cofactor [10]. However, only CBS contains a heme moiety, which may bind oxygen and make the enzyme function dependent on oxygen levels, as demonstrated in recombinant human CBS [11]. In addition, a range of biogenic amines, including serotonin, dopamine and noradrenalin bind the heme moiety of various enzymes, possibly modulating different cell functions [12]. Therefore, in this study we examined the involvement of CBS and H2S production in the protective effect of serotonin and dopamine on cold induced cellular damage in a cell line that showed the highest vulnerability to hypothermia, by studying cell numbers, caspase activity, and ROS formation. Moreover, we examined the expression of CBS in serotonin and dopamine treated rat tissues after static cold preservation in parallel to apoptosis and tissue acidosis/ischemia. ...
The protective effect of serotonin (30 µM, 15 min) and dopamine (20 µM,
15 min) pretreatment on hypothermic cell death is precluded by
inhibition of their respective transporters with fluoxetine. [prozac, SSRI] ...
Our study demonstrates that the increased H2S production in
cells is due to both upregulation and allosteric activation of CBS. The
upregulation of CBS expression following serotonin and dopamine
incubation is most likely caused via activation of mTOR kinase and
subsequent activation of the protein synthesis machinery. ...
In broader sense, our results identified a novel molecular link between major monoamine neurotransmitters and the H2S pathway. While prominently expressed in brain, a significant expression of the uptake pumps for serotonin and dopamine, SERT and DAT, was also found in peripheral organs, e.g. in liver, kidney and lung [45], [46]. Various drug classes profoundly affect serotoninergic and dopaminergic systems, including medicines such as anti-depressants (reviewed in [47]) but also recreational drugs including cocaine, amphetamines and XTC. In theory, any drug that interferes with synthesis, cellular uptake and/or metabolism of these neurotransmitters may affect H2S signaling. "
Do dopamine and serotonin regulate CBS expression under normothermic condition?
Is this relevant to SUDPAR?
Need to read more on H2S signalling in autonomic nervous system & interaction of H2S with NO signalling.
Cold intolerance is a symptom in severe MCAS (e.g., Shelly in Afrin's book) and elevated EPO. I experienced cold intolerance after trying Wim Hof breathing; maybe that's why it is supposed to be paired with cold acclimation.
~
I reviewed etiology of hyperemesis gravidarum - excessive vomiting during pregnancy, for which vit B6 is often prescribed. Despite being a terrible condition which sometimes requires hospitalization and is associated with learning problems in the children born, not much is known. Vit B6 has shown some efficacy in reducing nausea but not vomiting in HG. HG is associated with elevated GDF15 levels, which most likely plays a causal role. https://rarediseases.org/rare-diseases/hyperemesis-gravidarum
Since vomiting involves autonomic control & B6 is is a cofactor for CBS, I wondered if the same H2S signalling issue is a factor in HG, but it appears that increasing CBS activity actually increases GDF15 production (see ref. & quoted text below). Perhaps B6 decreases nausea symptoms by increasing serotonin production. Interestingly, estradiol increases CBS expression: https://pubmed.ncbi.nlm.nih.gov/30317617/
https://pubmed.ncbi.nlm.nih.gov/28923859/
"Other upregulated genes due to forced CBS overexpression have been shown to increase hypoxiaresponses (PER1,APLN), increased inflammation-mediated responses (ETS2,GDF15), cellular proliferation (CCND2,MAP3K5,PTK7,RPS6K2,E2F2,FGF19,MDK,KIT,JUNB,CXCR1,ELF3,FOS) cell migration (DDR1,PTK7,KIT,ELF3,S100A6,TNC), invasion (CDC42BPG,DDR1,HOXD11), and promotionof angiogenesis (ADM,ADM2,VEGFA,CXCR1,FOS).
How can upregulation of a single enzyme have such a broad impact on cellular phenotype? CBS plays an essential role in the synthesis of cysteine from homocysteine. In addition to being an essential amino acid constituent of cellular antioxidants such as glutathione, glutaredoxins, thioredoxins, and peroxredoxin, cysteine is an important source of endogenous H2S. Our data show that despite evidence for increase flux through the reverse trans-sulfuration pathway, there is not a significant change between the levels of cysteine in CBS2 cells when compared with vector-transduced controls (Fig. 2C). This is likely due to the increased CBS-dependent synthesis of H2S by CBS2 cells (Fig. 2D and E) and the accumulation of lanthionine (Table 1). H2S can directly stimulate cellular bioenergetics by contributing electrons to SQR in complex II to reduce coenzyme 10 to ubiquinol and, indirectly, by the posttranslational persulfidation of F1F0 of ATP synthase/Complex V with the result of enhancing ATP production (37–39). Persulfidation, also known as sulfhydration is the modification of cysteine residues on the target protein by H2Stoformapersulfide or–SSH group. H2S-mediated persulfidation also has been shown to increase the activity of GAPDH increasing glycolytic flux, to enhance actin polymerization (40) and to stimulate NF-kBp65activity inhibiting apoptosis (41). We show evidence for both increased glycolytic flux and resistance to apoptosis in NCM356cell overexpressing CBS. H2S has also been shown to impact gene expression by altering histone H3 acetylation and DNA methylation (42). Thus, H2S-dependent and independent (i.e.,increased O-GlcNAc of protein) processes could be responsible for the robust effects of CBS overexpression ..."
Perhaps it is not surprising that CBS polymorphisms (SNPs) have received some interest in the alternative health community, with both higher and lower CBS activity viewed as potential causes of health problems. https://www.mygenefood.com/blog/sulfur-cbs-genes-nutrition-radar/
~
If estradiol increases CBS expression, do phytoestrogens have any impact?
Alpha zearalanol was found to increase CBS activity, not by increasing expression, but by reducing nitration:
https://pubmed.ncbi.nlm.nih.gov/24783194/
"By the successfully established diet-induced hyperhomocysteinemia rat models, we found that, after α-zearalanol treatment, the activity of cystathionine β-synthase, the key enzyme in homocysteine metabolism, was significantly elevated and level of nitrative stress in liver was significantly reduced. In correlation with this, results also showed a decreased nitration level of cystathionine β-synthase in liver. Together data implied that alleviation of plasma homocysteine level by phytoestrogen α-zearalanol might be related to the reduction of cystathionine β-synthase nitration. "
Alpha zearalanol is also known as zeranol; according to Wikipedia it is a fungal phytoestrogen (mycoestrogen) used as a growth promoter in cattle and may increase breast cancer cell proliferation. Something that reduces nitrosative stress would be nice, but I guess not so much if it comes at the expense of cancer cell proliferation. A quick search of PubMed shows that zeranol has been investigated as a neuroprotective agent so it looks like another case of cancer vs. neurodegeneration.
~
Are CBS polymorphisms associated with HG? Apparently not:
https://rarediseases.org/rare-diseases/hyperemesis-gravidarum/
"Recent studies using a genetic approach have identified factors that are more likely to be involved in the etiology of HG. In particular, a study of over 53,000 23andMe research participants identified an association between genetic variants in the placenta and appetite genes GDF15 and IGFBP7 and HG. These findings were replicated in a separate cohort in whom variants in other genes were also found to be associated with HG including the GDF15 gene, the GDF15 receptor gene, GFRAL, localized to the vomiting center of the brain, and the progesterone receptor gene PGR. It is important to note that no association was found between HG and the hCG receptor. Additionally, studies have detected abnormally high blood levels of GDF15 (and IGFBP7 in one study) but not hCG in women with HG. Hyperthyroidism, nutrient deprivation, long-term fasting, potassium depletion and infection are all associated with HG pregnancies, and result in increasing GDF15 levels. Thus, there may be a cyclical effect whereby genetic factors contribute initially to abnormal levels of GDF15, which is then increased further by these other contributing factors."
Comments
Post a Comment