Sildenafil treatment (Homo sapiens)

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Label legend306, 283521, 25, 333211, 15420, 243527183623, 29NOS:sGCNucleusPDE4NOSAKT:PDE4:AKT1PRKNAKT2MitochondrialbiogenesisAMPGAPDH inhibitorsPRKG1Nitric oxideGTPTFAMPI3K CascadeZNF746Smooth musclerelaxationNRF1GUCY1A2GAPDHGMPPDE5PDE4ANO-signalingcGMPPDE4DGSK3BPPARGC1AMAPKpathwaytideglusibsildenafilPDE4CNOS1PDE4BPDE4inhibitors1214sGC:GUCY1B2GUCY1A1GUCY1B18, 162, 34Mitochondrialmembrane potentialCalciumhomeostasisOXPHOScapacityNeurogenesisSynaptic transmission7, 2219AKT3AKT10NOS31, 179Mitochondria5, 26NOS23, 31


Description

Pathway depicting the effect of sildenafil treatment. Related treatment options that target components of the same pathway are included. Developed in collaboration with Werner Koopman, Alessandro Prigione, Nael Nadif Kasri, and Peter-Bram 't Hoen.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
124488view12:16, 1 November 2022Cenna DoornbosReplaced incorrectly displayed symbols in bibliography.
124487view09:07, 1 November 2022Cenna DoornbosModified description
124481view12:48, 31 October 2022Cenna Doornbos
124480view11:16, 31 October 2022Cenna DoornbosAttached disconnected joints
124462view09:32, 29 October 2022EgonwMade multiple pathways clickable
124425view10:26, 27 October 2022Cenna DoornbosModified description
124424view09:17, 27 October 2022Cenna DoornbosOntology Term : 'hypertension' added !
124423view09:16, 27 October 2022Cenna DoornbosOntology Term : 'pulmonary hypertension' added !
124422view09:13, 27 October 2022Cenna DoornbosOntology Term : 'mitochondrial disease pathway' added !
124421view09:12, 27 October 2022Cenna DoornbosOntology Term : 'impotence' added !
124420view09:05, 27 October 2022Cenna DoornbosModified description
124417view08:57, 27 October 2022Cenna Doornbos
124416view08:53, 27 October 2022Cenna Doornbos
124415view08:51, 27 October 2022Cenna DoornbosCorrected connenctivity to pathways.
124414view08:44, 27 October 2022Cenna DoornbosAdded annotation identifiers for the interactions.
124400view08:32, 26 October 2022Cenna DoornbosNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AKT1GeneProductENSG00000142208 (Ensembl)
AKT2GeneProductENSG00000105221 (Ensembl)
AKT3GeneProductENSG00000117020 (Ensembl)
AMPMetaboliteCHEBI:16027 (ChEBI)
Calcium homeostasisPathwayWP4088 (WikiPathways)
GAPDH inhibitorsMetaboliteCHEBI:70817 (ChEBI)
GAPDHGeneProductENSG00000111640 (Ensembl)
GMPMetaboliteCHEBI:17345 (ChEBI)
GSK3BGeneProductENSG00000082701 (Ensembl)
GTPMetaboliteCHEBI:37565 (ChEBI)
GUCY1A1GeneProductENSG00000164116 (Ensembl) Also known as GUCY1A3 [uniprot:Q02108].
GUCY1A2GeneProductENSG00000152402 (Ensembl)
GUCY1B1GeneProductENSG00000061918 (Ensembl) Also known as GUCY1B3 [uniprot:Q02153].
GUCY1B2GeneProductENSG00000123201 (Ensembl)
MAPK pathwayPathwayWP382 (WikiPathways)
Mitochondrial biogenesisPathwayWP3331 (WikiPathways)
Mitochondrial membrane potentialPathwayR-HSA-8949215 (Reactome)
NO-signalingPathwayWP1850 (WikiPathways)
NOS1GeneProductENSG00000089250 (Ensembl)
NOS2GeneProductENSG00000007171 (Ensembl)
NOS3GeneProductENSG00000164867 (Ensembl) NOS3 is implicated in vascular smooth muscle relaxation through cGMP [PMID:1378832,PMID:20590592].
NRF1GeneProductENSG00000106459 (Ensembl)
NeurogenesisPathwayR-HSA-9675108 (Reactome)
Nitric oxideMetaboliteCHEBI:16480 (ChEBI)
OXPHOS capacityPathwayWP111 (WikiPathways)
PDE4 inhibitorsMetaboliteCHEBI:68844 (ChEBI)
PDE4AGeneProductENSG00000065989 (Ensembl)
PDE4BGeneProductENSG00000184588 (Ensembl)
PDE4CGeneProductENSG00000105650 (Ensembl)
PDE4DGeneProductENSG00000113448 (Ensembl)
PDE5GeneProductENSG00000138735 (Ensembl) Inhibition of cGMP degradation by PDE5 increases cGMP availability [PMID:9714779].
PI3K CascadePathwayWP4448 (WikiPathways) AKT is activated through phosphorylation upon recruitement to the cell membrane
PPARGC1AGeneProductENSG00000109819 (Ensembl) Alternative name is PGC1A [uniprot:Q9UBK2]
PRKG1GeneProductENSG00000185532 (Ensembl)
PRKNGeneProductENSG00000185345 (Ensembl)
Smooth muscle relaxationPathwayR-HSA-418457 (Reactome)
Synaptic transmissionPathwayR-HSA-112310.5 (Reactome)
TFAMGeneProductENSG00000108064 (Ensembl)
ZNF746GeneProductENSG00000181220 (Ensembl)
cGMPMetaboliteCHEBI:16356 (ChEBI)
sildenafilMetaboliteCHEBI:9139 (ChEBI)
tideglusibMetaboliteCHEBI:147398 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
AKTMitochondrial membrane potentialArrowR-HSA-04151 (Reactome) The family of AKT proteins stabalize mitochondrial membrane potential through TCL1A [uniprot:P56279] and TCL1B [unirprot:O95988]. [PMID:10983986,PMID:11839817]
AKTNeurogenesisArrowR-HSA-157118 (Reactome)
  • Negative regulation of neuronal death [GO:1901215]
  • Regulation of neuron projection development [GO:0010975]
AKTPPARGC1AArrowR-HSA-04151 (Reactome)
GAPDH inhibitorsGAPDHmim-inhibitionCHEBI:70817 (ChEBI)
GAPDHAKTmim-stimulationEBI-7982916 (IntAct) GAPDH can bind AKT to limit dephosphorylation, prolonging AKT activity and therefor increase mitochondrial membrane potential stabilization [PMID:23645209].
GTPcGMPmim-conversion4.6.1.2 (BRENDA)
NOSGAPDHArrowEBI-10091848 (IntAct)
NOSNitric oxidemim-conversion1.14.13.39 (BRENDA) The family of nitric oxide synthases produce nitric oxide (NO) from L-argine, oxigen and NAPDH [PMID:1722402,PMID:1662386].
NRF1TFAMmim-transcription-translationWP3331 (WikiPathways)
Nitric oxidesGCmim-bindingR-HSA-392154 (Reactome) Soluble guanylyl cyclases (sGC) are activated by nitric oxide (NO) [PMID:9742212].
PDE4 inhibitorsPDE4TBarCHEBI:68844 (ChEBI)
PDE4AMPmim-catalysis3.1.4.53 (BRENDA) The family of PDE4s (cAMP-specific 3',5'-cyclic phosphodiesterases) hydrolyse cAMP into AMP.
PDE5mim-catalysis3.1.4.35 (BRENDA)
  • Inhibition of cGMP degradation by PDE5 increases cGMP availability [PMID:9714779].
PPARGC1ANRF1mim-transcription-translationWP3331 (WikiPathways) Transcriptional coactivator
PRKG1AKTArrowR-HSA-1257604 (Reactome)
PRKNZNF746ArrowEBI-3862570 (IntAct)
TFAMOXPHOS capacityArrowWP3331 (WikiPathways)
ZNF746PPARGC1Amim-inhibitionEBI-3989372 (IntAct) Repressed transcription of PGC-1-alpha (PPARGC1A), thereby playing a role in regulation of neuron death [PMID:21376232]
cGMPArrow2.7.11.12 (BRENDA)
cGMPSmooth muscle relaxationArrowR-HSA-418457 (Reactome) An increase in cGMP leads to smooth muscle relaxation and therefore relieve the symptoms of erectile disfunction [PMID:2545495,PMID:8813924].
cGMPmim-conversion3.1.4.35 (BRENDA) cGMP is converted into GMP through hydrolysis by PDE5 [PMID:7870041].
sGCPRKG1ArrowR-HSA-392154 (Reactome)
sGCmim-stimulation4.6.1.2 (BRENDA) sGCs catalyze the conversion of GTP into GMP.
sildenafilPDE5TBarDB00203 (DrugBank)
tideglusibGSK3BTBarDB12129 (DrugBank) Glycogen synthase kinase 3beta (GSK3beta) tideglusib (NP031112) has anti-inflammatory and neuroprotective properties [PMID:17522320].
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