Estradiol regulation in porto-sinusoidal vascular disease (Homo sapiens)

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3 ' Vascular Endothelial Cell (e.g. in resistance artery)ERαCa2+SP3ApaminSP1KCNN3K+Endothelial HyperpolarizationEstradiolX3 ' 5 '5 'SK3 channelCALM1K+Endothelial Derived Hyperpolarization (EDH) of Vascular Smooth Muscle cellsVascular DilationLowering Blood PressureVascular Smoot Muscle Cell (e.g. in resistance artery)Nucleus


Description

Porto-Sinusoidal Vascular Disease (PSVD) is a rare disease, meaning that it only affects less than 1 in 2000 citizens (European standard) (Griffon et al., 2016). It is characterized by signs of presinusoidal portal hypertension without cirrhosis, where the cause of the hypertension is unknown (Lee et al., 2016; Schouten et al., 2011). Based on that what is known about the etiology of PSVD, the development can be categorized into five groups: Immunological disorders, chronic infections, exposure to medications/toxins, prothrombic conditions, and genetic predisposition (Schouten et al., 2015). In practice, there is often multifactorial causation of the disease (Siramolpiwat et al., 2016).

Currently, this pathway describes a mutation in the KCNN3 gene that is hypothesized to result in genetic predisposition to PSVD (Koot et al., 2016).

PSVD has also been referred as: - Idiopathic Non-Cirrhotic Portal Hypertension (INCPH)

- Hepatoportal Sclerosis

- Incomplete Septal Cirrhosis

- Obliterative Portal Venopathy

- Partial Nodular Transformation

- Non-cirrhotic portal fibrosis

- Nodular Regenerative Hyperplasia (NRH)

- Idiopathic portal hypertension

(Schouten et al., 2015; Siramolpiwat et al., 2016; Besmond et al., 2017)

Literature of pathway description:

- Griffon N, Schuers M, Dhombres F, Merabti T, Kerdelhué G, Rollin L, et al. Searching for rare diseases in PubMed: a blind comparison of Orphanet expert query and query based on terminological knowledge. BMC Med Inform Decis Mak. 2016 Aug 2;16:101.

- Besmond C, Valla D, Hubert L, Poirier K, Grosse B, Guettier C, et al. Mutations in the novel gene FOPV are associated with familial autosomal dominant and non-familial obliterative portal venopathy. Liver Int. 2018 Feb;38(2):358–64.

- Koot BGP, Alders M, Verheij J, Beuers U, Cobben JM. A de novo mutation in KCNN3 associated with autosomal dominant idiopathic non-cirrhotic portal hypertension. J Hepatol. 2016 Apr;64(4):974–7.

- Lee H, Rehman AU, Fiel MI. Idiopathic Noncirrhotic Portal Hypertension: An Appraisal. J Pathol Transl Med. 2016 Jan;50(1):17–25.

- Schouten JNL, Garcia-Pagan JC, Valla DC, Janssen HLA. Idiopathic noncirrhotic portal hypertension. Hepatology. 2011 Sep 2;54(3):1071–81.

- Schouten JNL, Verheij J, Seijo S. Idiopathic non-cirrhotic portal hypertension: a review. Orphanet J Rare Dis. 2015 May 30;10:67.

- Seijo S. Idiopathic non-cirrhotic portal hypertension. J Rare Dis Res Treat. 2016 Nov 1;1(3):10–6.

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Bibliography

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  1. Gu M, Zhu Y, Yin X, Zhang DM; ''Small-conductance Ca2+-activated K+channels: insights into their roles in cardiovascular disease.''; Exp Mol Med, 2018 PubMed Europe PMC Scholia
  2. Griffon N, Schuers M, Dhombres F, Merabti T, Kerdelhué G, Rollin L, Darmoni SJ; ''Searching for rare diseases in PubMed: a blind comparison of Orphanet expert query and query based on terminological knowledge.''; BMC Med Inform Decis Mak, 2016 PubMed Europe PMC Scholia
  3. Schouten JN, Verheij J, Seijo S; ''Idiopathic non-cirrhotic portal hypertension: a review.''; Orphanet J Rare Dis, 2015 PubMed Europe PMC Scholia
  4. Morikawa H, Morrisett RA; ''Ethanol action on dopaminergic neurons in the ventral tegmental area: interaction with intrinsic ion channels and neurotransmitter inputs.''; Int Rev Neurobiol, 2010 PubMed Europe PMC Scholia
  5. Schouten JN, Garcia-Pagan JC, Valla DC, Janssen HL; ''Idiopathic noncirrhotic portal hypertension.''; Hepatology, 2011 PubMed Europe PMC Scholia
  6. Taylor MS, Bonev AD, Gross TP, Eckman DM, Brayden JE, Bond CT, Adelman JP, Nelson MT; ''Altered expression of small-conductance Ca2+-activated K+ (SK3) channels modulates arterial tone and blood pressure.''; Circ Res, 2003 PubMed Europe PMC Scholia
  7. Weisbrod D; ''Small and Intermediate Calcium Activated Potassium Channels in the Heart: Role and Strategies in the Treatment of Cardiovascular Diseases.''; Front Physiol, 2020 PubMed Europe PMC Scholia
  8. Ledoux J, Werner ME, Brayden JE, Nelson MT; ''Calcium-activated potassium channels and the regulation of vascular tone.''; Physiology (Bethesda), 2006 PubMed Europe PMC Scholia
  9. Besmond C, Valla D, Hubert L, Poirier K, Grosse B, Guettier C, Bernard O, Gonzales E, Jacquemin E; ''Mutations in the novel gene FOPV are associated with familial autosomal dominant and non-familial obliterative portal venopathy.''; Liver Int, 2018 PubMed Europe PMC Scholia
  10. Sith Siramolpiwat, Susana Seijo; ''Idiopathic non-cirrhotic portal hypertension''; Journal of Rare Diseases Research & Treatment, 2016
  11. Köhler M, Hirschberg B, Bond CT, Kinzie JM, Marrion NV, Maylie J, Adelman JP; ''Small-conductance, calcium-activated potassium channels from mammalian brain.''; Science, 1996 PubMed Europe PMC Scholia
  12. Jacobson D, Pribnow D, Herson PS, Maylie J, Adelman JP; ''Determinants contributing to estrogen-regulated expression of SK3.''; Biochem Biophys Res Commun, 2003 PubMed Europe PMC Scholia
  13. Köhler R, Ruth P; ''Endothelial dysfunction and blood pressure alterations in K+-channel transgenic mice.''; Pflugers Arch, 2010 PubMed Europe PMC Scholia
  14. Koot BG, Alders M, Verheij J, Beuers U, Cobben JM; ''A de novo mutation in KCNN3 associated with autosomal dominant idiopathic non-cirrhotic portal hypertension.''; J Hepatol, 2016 PubMed Europe PMC Scholia
  15. Lee H, Rehman AU, Fiel MI; ''Idiopathic Noncirrhotic Portal Hypertension: An Appraisal.''; J Pathol Transl Med, 2016 PubMed Europe PMC Scholia
  16. Pierce SL, England SK; ''SK3 channel expression during pregnancy is regulated through estrogen and Sp factor-mediated transcriptional control of the KCNN3 gene.''; Am J Physiol Endocrinol Metab, 2010 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
135156view00:03, 7 August 2024EweitzClear cache to fix board height
135155view00:02, 7 August 2024EweitzEconomize layout
135154view23:58, 6 August 2024EweitzEconomize layout
135153view23:56, 6 August 2024EweitzEconomize layout
127926view18:47, 17 January 2024Khanspersdecreased board height
127925view18:45, 17 January 2024Khanspersdecreased board height
127924view04:57, 17 January 2024EweitzTrim diagram perimeter margin, deconvolute Apamin interaction
127923view04:51, 17 January 2024EweitzEconomize layout
127922view04:33, 17 January 2024EweitzFix typo (smoot -> smooth), standardize case
127921view04:31, 17 January 2024EweitzFix misnamed gene: ER1 -> ESR1
127920view04:27, 17 January 2024EweitzOntology Term : 'vascular associated smooth muscle cell' added !
127919view04:25, 17 January 2024EweitzOntology Term : 'endothelial cell' added !
127480view14:02, 8 October 2023LarsgwUpdate DataNode annotations
127479view13:58, 8 October 2023EgonwChEBI id for K+ instead of the "K" atom
123952view11:31, 7 September 2022EweitzModified description
123951view11:27, 7 September 2022EweitzModified title
123627view08:25, 7 August 2022EgonwModified title
123338view19:27, 16 July 2022AlexanderPicoOntology Term : 'hypertension pathway' added !
123337view19:27, 16 July 2022AlexanderPicoOntology Term : 'vascular disease' added !
123336view19:25, 16 July 2022AlexanderPicoModified description
123084view15:33, 27 June 2022ChristeldeVriesChanged display name of ERα into ER1
123081view07:22, 27 June 2022ChristeldeVriesModified title
123077view10:31, 24 June 2022ChristeldeVriesAnnotation added
123076view10:25, 24 June 2022FehrhartOntology Term : 'disease pathway' added !
123075view10:25, 24 June 2022FehrhartOntology Term : 'portal hypertension' added !
123073view10:14, 24 June 2022ChristeldeVriesModified description
123072view10:12, 24 June 2022ChristeldeVriesModified description
123071view10:10, 24 June 2022ChristeldeVriesAdded and updated references
122897view14:27, 30 May 2022ChristeldeVriesModified title
122895view10:56, 30 May 2022ChristeldeVriesModified description
122894view10:56, 30 May 2022ChristeldeVriesModified description
122893view10:55, 30 May 2022ChristeldeVriesModified description
122892view10:54, 30 May 2022ChristeldeVriesModified description
122883view10:35, 28 May 2022ChristeldeVriesRemoved Enhancer and Promoter
122882view09:38, 28 May 2022ChristeldeVriesAdjusted LayOut
122881view09:25, 28 May 2022ChristeldeVriesUpdated Annotation
122872view16:00, 27 May 2022ChristeldeVriesUpdated interactions SP1, SP3, ERalpha
122861view11:33, 25 May 2022ChristeldeVriesReorganisation
122860view07:17, 25 May 2022ChristeldeVriesReorganisation
122810view09:34, 20 May 2022ChristeldeVriesChange visualisation of gene stimulation
122807view06:08, 19 May 2022ChristeldeVriesAdded probable genetic component
122776view11:53, 13 May 2022ChristeldeVriesUpdated references
122764view11:43, 12 May 2022ChristeldeVriesNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ApaminMetabolite16133797 (PubChem-compound)
CALM1ProteinP0DP23 (Uniprot-TrEMBL)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
ERαProteinP03372 (Uniprot-TrEMBL)
Endothelial Derived Hyperpolarization (EDH) of Vascular Smooth Muscle cells
Endothelial HyperpolarizationQ66026601 (Wikidata)
EstradiolMetaboliteCHEBI:16469 (ChEBI)
K+MetaboliteCHEBI:26216 (ChEBI)
KCNN3GeneProductENSG00000143603 (Ensembl) About:

A single nucleotide substitution (SNP) c.1348G>C in the KCNN3 gene was found in a father with INCPH and three of his children that were tested with Sanger- and whole exome sequencing. This three children had developed signs of INCPH in the first ten years of their lives. A full sister of one of the girls had no complaints and did not participate in the examinations. Ultrasound and livertests of the paternal grandparents showed no abnormalities of the liver. (Koot et al. 2016)

KCNN genes are expressed in neurons, epithelium, endothelium of the vasculature, and several types of smooth muscle. The SK3 channel, which is a gene product of the KCNN3 gene, is involved in vascular tone- and blood pressure regulation. Calcium induced activation of the SK3 channel will cause hyperpolarization of endothelial cells, resulting in hyperpolarization of the adjacent muscle cell, which is also known as a endothelium-derived hyperpolarizing factor (EDHF). This hyperpolization of the muscle cells will then result in dilation in resistance arteries (Ledoux et al. 2006; Kohler et al. 2010). The level of SK3 channel expression in endothelial cells was found to be important for vascular tone and blood pressure in mice. (Taylor et al. 2003)

Gene transcription: Two binding sites for the SP1 and SP3 transcription factors are present in the promotor region of the KCNN3 gene in mice. SP1 and SP3 compete to regulate the expression of the KCNN3 gene, influenced by the environment of the promotors. SP1 activates the expression of the gene, and SP3 inhibits the expression of the gene (Pierce et al., 2010; Xiong et al., 2020) . It was found that ERα seems to stimulate the transcription KCNN3 through these transcription factors (Jacobson et al., 2003).

Lowering Blood PressureQ69904902 (Wikidata)
SK3 channelProteinQ9UGI6 (Uniprot-TrEMBL) Also referred to as:

Small-conductance Ca2+- activated K+ (SK) channel Small conductance calcium-activated potassium channel protein 3 SK3 channel SKCa 3 KCa channel

About: The SK3 channel is important for afterhyperpolarization following an action potential. SK3 channels consist of six transmembrane segments that are connected via a single pore loop. The N-termini and the C-termini are both located at the intracellular side of the membrane. A calmodulin molecule is located at the C-termini of the SK3 channel via a CaM-binding domain. Calmodulin will activate the SK3 channel upon binding of Ca2+. SK3 channels are voltage-independent.

(Gu et al. 2018; Köhler et al. 1996; Weisbrod, 2020)
SP1ProteinP08047 (Uniprot-TrEMBL)
SP3ProteinQ02447 (Uniprot-TrEMBL)
Vascular Dilation

Annotated Interactions

No annotated interactions

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