Sildenafil treatment (Homo sapiens)

From WikiPathways

Jump to: navigation, search
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


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.

Quality Tags

Ontology Terms



View all...
  1. Kunstle G, Laine J, Pierron G, Kagami Si S, Nakajima H, Hoh F, Roumestand C, Stern MH, Noguchi M; ''Identification of Akt association and oligomerization domains of the Akt kinase coactivator TCL1.''; Mol Cell Biol, 2002 PubMed Europe PMC Scholia
  2. Livi GP, Kmetz P, McHale MM, Cieslinski LB, Sathe GM, Taylor DP, Davis RL, Torphy TJ, Balcarek JM; ''Cloning and expression of cDNA for a human low-Km, rolipram-sensitive cyclic AMP phosphodiesterase.''; Mol Cell Biol, 1990 PubMed Europe PMC Scholia
  3. Diaz B, Serna J, De Pablo F, de la Rosa EJ; ''In vivo regulation of cell death by embryonic (pro)insulin and the insulin receptor during early retinal neurogenesis.''; Development, 2000 PubMed Europe PMC Scholia
  4. Jacquin MA, Chiche J, Zunino B, Beneteau M, Meynet O, Pradelli LA, Marchetti S, Cornille A, Carles M, Ricci JE; ''GAPDH binds to active Akt, leading to Bcl-xL increase and escape from caspase-independent cell death.''; Cell Death Differ, 2013 PubMed Europe PMC Scholia
  5. Goffart S, Wiesner RJ; ''Regulation and co-ordination of nuclear gene expression during mitochondrial biogenesis.''; Exp Physiol, 2003 PubMed Europe PMC Scholia
  6. Blount MA, Beasley A, Zoraghi R, Sekhar KR, Bessay EP, Francis SH, Corbin JD; ''Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation.''; Mol Pharmacol, 2004 PubMed Europe PMC Scholia
  7. Galera-Monge T, Zurita-Diaz F, Canals I, Hansen MG, Rufian-Vazquez L, Ehinger JK, Elmer E, Martin MA, Garesse R, Ahlenius H, Gallardo ME; ''''; , PubMed Europe PMC Scholia
  8. Schmidt HH, Murad F; ''Purification and characterization of a human NO synthase.''; Biochem Biophys Res Commun, 1991 PubMed Europe PMC Scholia
  9. Virbasius JV, Scarpulla RC; ''Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis.''; Proc Natl Acad Sci U S A, 1994 PubMed Europe PMC Scholia
  10. Cohen MM Jr; ''''; , PubMed Europe PMC Scholia
  11. Scott JD; ''Cyclic nucleotide-dependent protein kinases.''; Pharmacol Ther, 1991 PubMed Europe PMC Scholia
  12. Luna-Medina R, Cortes-Canteli M, Sanchez-Galiano S, Morales-Garcia JA, Martinez A, Santos A, Perez-Castillo A; ''NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disorders.''; J Neurosci, 2007 PubMed Europe PMC Scholia
  13. Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C; ''Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesteraseinhibitor for the treatment of penile erectile dysfunction.''; Int J Impot Res, 1996 PubMed Europe PMC Scholia
  14. Beltman J, Becker DE, Butt E, Jensen GS, Rybalkin SD, Jastorff B, Beavo JA; ''''; , PubMed Europe PMC Scholia
  15. Hartell NA; ''cGMP acts within cerebellar Purkinje cells toproduce long term depression via mechanisms involving PKC and PKG.''; Neuroreport, 1994 PubMed Europe PMC Scholia
  16. Zembowicz A, Hecker M, Macarthur H, Sessa WC, Vane JR; ''Nitric oxide and another potent vasodilator are formed from NG-hydroxy-L-arginine by cultured endothelial cells.''; Proc Natl Acad Sci U S A, 1991 PubMed Europe PMC Scholia
  17. Laine J, Kunstle G, Obata T, Sha M, Noguchi M; ''The protooncogene TCL1 is an Akt kinase coactivator.''; Mol Cell, 2000 PubMed Europe PMC Scholia
  18. Olson BL, Hock MB, Ekholm-Reed S, Wohlschlegel JA, Dev KK, Kralli A, Reed SI; ''SCFCdc4 acts antagonistically to the PGC-1alpha transcriptional coactivator by targeting it for ubiquitin-mediated proteolysis.''; Genes Dev, 2008 PubMed Europe PMC Scholia
  19. Bird MJ, Thorburn DR, Frazier AE; ''Modelling biochemical features of mitochondrial neuropathology.''; Biochim Biophys Acta, 2014 PubMed Europe PMC Scholia
  20. Boolell M, Gepi-Attee S, Gingell JC, Allen MJ; ''''; , PubMed Europe PMC Scholia
  21. Sporbert A, Mertsch K, Smolenski A, Haseloff RF, Schonfelder G, Paul M, Ruth P, Walter U, Blasig IE; ''Phosphorylation of vasodilator-stimulated phosphoprotein: a consequence of nitric oxide- and cGMP-mediated signal transduction in brain capillary endothelial cells and astrocytes.''; Brain Res Mol Brain Res, 1999 PubMed Europe PMC Scholia
  22. Stevic N, Maalouf J, Argaud L, Gallo-Bona N, Lo Grasso M, Gouriou Y, Gomez L, Crola Da Silva C, Ferrera R, Ovize M, Cour M, Bidaux G; ''Cooling Uncouples Differentially ROS Production from Respiration and Ca2+Homeostasis Dynamic in Brain and Heart Mitochondria.''; Cells, 2022 PubMed Europe PMC Scholia
  23. Chung HH, Dai ZK, Wu BN, Yeh JL, Chai CY, Chu KS, Liu CP, Chen IJ; ''''; , PubMed Europe PMC Scholia
  24. Furchgott RF, Vanhoutte PM; ''Endothelium-derived relaxing and contracting factors.''; FASEB J, 1989 PubMed Europe PMC Scholia
  25. Rivero-Vilches FJ, de Frutos S, Saura M, Rodriguez-Puyol D, Rodriguez-Puyol M; ''Differential relaxing responses to particulate or soluble guanylyl cyclase activation on endothelial cells: a mechanism dependent on PKG-I alpha activation by NO/cGMP.''; Am J Physiol Cell Physiol, 2003 PubMed Europe PMC Scholia
  26. Taherzadeh-Fard E, Saft C, Akkad DA, Wieczorek S, Haghikia A, Chan A, Epplen JT, Arning L; ''PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease.''; Mol Neurodegener, 2011 PubMed Europe PMC Scholia
  27. Borniquel S, Valle I, Cadenas S, Lamas S, Monsalve M; ''Nitric oxide regulates mitochondrial oxidative stress protection via the transcriptional coactivator PGC-1alpha.''; FASEB J, 2006 PubMed Europe PMC Scholia
  28. Loughney K, Hill TR, Florio VA, Uher L, Rosman GJ, Wolda SL, Jones BA, Howard ML, McAllister-Lucas LM, Sonnenburg WK, Francis SH, Corbin JD, Beavo JA, Ferguson K; ''Isolation and characterization of cDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3',5'-cyclic nucleotide phosphodiesterase.''; Gene, 1998 PubMed Europe PMC Scholia
  29. Janssens SP, Shimouchi A, Quertermous T, Bloch DB, Bloch KD; ''''; , PubMed Europe PMC Scholia
  30. Zabel U, Weeger M, La M, Schmidt HH; ''Human soluble guanylate cyclase: functional expression and revised isoenzyme family.''; Biochem J, 1998 PubMed Europe PMC Scholia
  31. Owada Y, Utsunomiya A, Yoshimoto T, Kondo H; ''Expression of mRNA for Akt, serine-threonine protein kinase, in the brain during development and its transient enhancement following axotomy of hypoglossal nerve.''; J Mol Neurosci, 1997 PubMed Europe PMC Scholia
  32. Giuili G, Scholl U, Bulle F, Guellaen G; ''Molecular cloning of the cDNAs coding for the two subunits of soluble guanylyl cyclase from human brain.''; FEBS Lett, 1992 PubMed Europe PMC Scholia
  33. Zhan X, Li D, Johns RA; ''Immunohistochemical evidence for the NO cGMP signaling pathway in respiratory ciliated epithelia of rat.''; J Histochem Cytochem, 1999 PubMed Europe PMC Scholia
  34. Lario PI, Bobechko B, Bateman K, Kelly J, Vrielink A, Huang Z; ''Purification and characterization of the human PDE4A catalytic domain (PDE4A330-723) expressed in Sf9 cells.''; Arch Biochem Biophys, 2001 PubMed Europe PMC Scholia
  35. Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, Troconso JC, Dawson VL, Dawson TM; ''''; , PubMed Europe PMC Scholia
  36. Takimoto E, Champion HC, Belardi D, Moslehi J, Mongillo M, Mergia E, Montrose DC, Isoda T, Aufiero K, Zaccolo M, Dostmann WR, Smith CJ, Kass DA; ''cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism.''; Circ Res, 2005 PubMed Europe PMC Scholia


View all...
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


View all...
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

View all...
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].
Personal tools