Estradiol regulation in porto-sinusoidal vascular disease (WP5235)

Homo sapiens

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Porto-sinusoidal vascular disease (PSVD) is a rare disease (Schouten et al., 2015), affecting 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, its development can be categorized into five groups: immunological disorders, chronic infections, exposure to medications or toxins, prothrombic conditions, and genetic predisposition (Schouten et al., 2015). In practice, the disease has multiple contributing factors (Siramolpiwat et al., 2016). 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), and idiopathic portal hypertension (Schouten et al., 2015; Siramolpiwat et al., 2016; Besmond et al., 2017).

Authors

ChristeldeVries , Friederike Ehrhart , Alex Pico , Egon Willighagen , Eric Weitz , Lars Willighagen , and Kristina Hanspers

Activity

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Organisms

Homo sapiens

Communities

Diseases

Annotations

Disease Ontology

portal hypertension vascular disease

Cell Type Ontology

vascular associated smooth muscle cell endothelial cell

Pathway Ontology

hypertension pathway disease pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
Ca2+ Metabolite chebi:29108
Apamin Metabolite pubchem.compound:16133797 The SK3 channel is apamin sensitive. The peptide toxin apamin, present in bee venom, blocks the SK3 channels, reducing hyperpolarization of the cells (Morikawa, 2010; Weisbrod, 2020)
Estradiol Metabolite chebi:16469
K+ Metabolite chebi:29103
KCNN3 GeneProduct ensembl:ENSG00000143603 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. These 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 liver tests of the paternal grandparents showed no abnormalities of the liver. (Koot et al. 2015) 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 an endothelium-derived hyperpolarizing factor (EDHF). This hyperpolarization 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 stimulates the transcription KCNN3 through these transcription factors (Jacobson et al., 2003).
ESR1 Protein uniprot:P03372
SP1 Protein uniprot:P08047
SP3 Protein uniprot:Q02447
SK3 Protein uniprot:Q9UGI6 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. One channel is made from four monomers which all contain six transmembrane segments, 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 not voltage-dependent. (Gu et al. 2018; Köhler et al. 1996; Weisbrod, 2020) 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 an endothelium-derived hyperpolarizing factor (EDHF). This hyperpolarization 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)
CALM1 Protein uniprot:P0DP23

References

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  3. Altered expression of small-conductance Ca2+-activated K+ (SK3) channels modulates arterial tone and blood pressure. Taylor MS, Bonev AD, Gross TP, Eckman DM, Brayden JE, Bond CT, et al. Circ Res. 2003 Jul 25;93(2):124–31. PubMed Europe PMC Scholia
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