Chronic hyperglycemia impairment of neuron function (Homo sapiens)

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31Excessiveglucosefrom GliaGrowthconeAGEMMP11ProteinKinasesPRKCABDNFMMP14MMP1MMP9ETCMMP13MMP19MMP21MMP20NADHMMP10PRKCQSNAP25PKCMMP8PRKCDSensitizationHyperexcitationMMP7ATPNADPNa⁺/K⁺-ATPaseMMP16MMP12SorbitolADPMMP25FructoseMMP28Urea CycleMMP24MMP27TKRC3MMP15NADBDNF-TrkBsignalingPRKCZMMP23BPGE2PRKCEPRKCBMMP3Na+NADPHRAGEcytokinesNADPHoxidaseTRPV1SNAPProteinsPRKCIGlut-1DNAPRKCHPRKCGGPCRPRKD3MMP17O2- radicalMMP2O2- radical2, 4Glut-3glucoseglucoseglucoseROSProteinSynthesisMicroangiopathyBlood VesselCa2+K+K+Na+Na+K+ionimbalanceROSe-NONRSINOSAGE2, 4MMPROSMMPTRPA1NMDANav1.63Nav1.7Nav1.8BDNFRfrom GliaPKCSNAPProteins


Description

Chronic excess of glucose (chronic hyperglycemia) impairs neuron function via the polyol pathway, causing ROS and RNS eventually. These activate nuclear transcription factors that increase the expression of ion channel transducers TRP and NaV and impairs their capacity to self-repair. Meanwhile, microglia-released cytokines, ATP, BDNF, and NO stimulate GPCR and tyrosine kinase receptors. This causes a signaling cascade leading to the phosphorylation of TRP and NaV channels, further distorting normal biology.

Quality Tags

Ontology Terms

 

Bibliography

  1. King RH; ''The role of glycation in the pathogenesis of diabetic polyneuropathy.''; Mol Pathol, 2001 PubMed Europe PMC Scholia
  2. Perrone A, Giovino A, Benny J, Martinelli F; ''Advanced Glycation End Products (AGEs): Biochemistry, Signaling, Analytical Methods, and Epigenetic Effects.''; Oxid Med Cell Longev, 2020 PubMed Europe PMC Scholia
  3. Rajchgot T, Thomas SC, Wang JC, Ahmadi M, Balood M, Crosson T, Dias JP, Couture R, Claing A, Talbot S; ''Neurons and Microglia; A Sickly-Sweet Duo in Diabetic Pain Neuropathy.''; Front Neurosci, 2019 PubMed Europe PMC Scholia
  4. Turner DP; ''Advanced glycation end-products: a biological consequence of lifestyle contributing to cancer disparity.''; Cancer Res, 2015 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
124551view12:16, 8 November 2022EweitzModified description
124085view20:17, 16 September 2022EgonwMore pathways clickable
124074view06:10, 16 September 2022EgonwMade a pathway clickable
124034view14:49, 14 September 2022DeSlOntology Term : 'diabetic neuropathy' added !
124033view14:48, 14 September 2022DeSlAddedmissing IDs for glucose nodes, TRPV1 and TRPA1
124032view14:44, 14 September 2022DeSlAdded InterPro ID for NMDA
124031view14:42, 14 September 2022DeSlAdded more details on NMDA; not possible to add EC code
124030view14:38, 14 September 2022DeSlAdded ID for PKC
124029view14:37, 14 September 2022DeSlAdded some more details on NRS
124028view14:24, 14 September 2022DeSlAdded details on iNOS
124027view14:21, 14 September 2022DeSlAdded ETC ID for OXPHOS system PW
124026view14:19, 14 September 2022DeSlAdded note for BDNFR, added PW ID for DNA
124025view14:14, 14 September 2022DeSlAdded sodium-potassium pump annotation
124013view06:01, 13 September 2022EgonwAnother ROS
124012view06:00, 13 September 2022EgonwFinal clean up: removed a few incorrect annotations; grouped PKC and SNAP proteins
124011view05:56, 13 September 2022EgonwMoved the PKC proteins together
124010view05:20, 13 September 2022EgonwA few more identifiers
124009view05:09, 13 September 2022EgonwTwo more identifiers: cytokines, and C3 (which was correct afterall)
124008view05:05, 13 September 2022EgonwAdded an AGE/RAGE interaction reference
124007view04:57, 13 September 2022EgonwAGE := advanced glycation end-product
124006view04:50, 13 September 2022EgonwMissing info: protein typing; missing data source
124005view04:44, 13 September 2022EgonwSmall updates: BDNF identifier, link to related pathway, and remove wrong C3
124003view16:03, 12 September 2022EgonwThree more identifiers
124002view15:58, 12 September 2022EgonwModified description
124001view13:33, 11 September 2022EgonwLast bits of missing content. Much bio annotation missing, including references for the interactions
123999view09:08, 11 September 2022EgonwSome further work, annotations, MMPs together.
123998view07:02, 11 September 2022EgonwOntology Term : 'neuron' added !
123997view07:01, 11 September 2022EgonwOntology Term : 'hyperglycemia' added !
123996view07:01, 11 September 2022EgonwOntology Term : 'disease pathway' added !
123995view06:59, 11 September 2022EgonwAdded identifier for the interesting gene here
123994view06:56, 11 September 2022EgonwMore content drawn in
123993view19:20, 10 September 2022AlexanderPicoAdded disease from PFOCR
123992view19:18, 10 September 2022AlexanderPicoAdded chemicials from PFOCR
123991view18:41, 10 September 2022AlexanderPicoimported PFOCR genes with xrefs
123988view11:14, 10 September 2022EgonwNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteQ185253 (Wikidata)
AGEMetabolite84123 (ChEBI)
ATPMetaboliteQ80863 (Wikidata)
BDNF-TrkB signalingPathwayWP3676 (WikiPathways)
BDNFProtein627 (Entrez Gene)
BDNFRProteinreceptor, not specified in publication [PMID: 30766472] which specific one. "BDNF binds at least two receptors on the surface of cells that are capable of responding to this growth factor, TrkB (pronounced "Track B") and the LNGFR (for low-affinity nerve growth factor receptor, also known as p75).[26] It may also modulate the activity of various neurotransmitter receptors, including the Alpha-7 nicotinic receptor." Source: https://en.wikipedia.org/wiki/Brain-derived_neurotrophic_factor .
C3Protein718 (Entrez Gene)
Ca2+Metabolite29108 (ChEBI)
DNAPathwayWP466 (WikiPathways)
ETCPathwayWP111 (WikiPathways) Assumed to mean 'Electron Transport Chain'
FructoseMetaboliteQ61738075 (Wikidata)
GPCRProteinQ38173 (Wikidata)
Glut-1Protein6513 (Entrez Gene)
Glut-3Protein6515 (Entrez Gene)
INOSProteinP35228 (Uniprot-TrEMBL) Assumed to represent one of the nitric oxide sunthases (due to connection to NO metabolite); the xNOS family of enzymes catalyzes the production of nitric oxide from L-arginine. Publication [PMID: 30766472] states :"Nitric oxide (NO) is a potent vasoactive gas formed by three nitric oxide synthase (NOS) isoenzymes: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS)"
K+Metabolite29103 (ChEBI)
MMPProtein
MMP10GeneProduct4319 (Entrez Gene)
MMP11GeneProduct4320 (Entrez Gene)
MMP12GeneProduct4321 (Entrez Gene)
MMP13GeneProduct4322 (Entrez Gene)
MMP1GeneProduct4312 (Entrez Gene)
MMP14GeneProduct4323 (Entrez Gene)
MMP15GeneProduct4324 (Entrez Gene)
MMP16GeneProduct4325 (Entrez Gene)
MMP17GeneProduct4326 (Entrez Gene)
MMP19GeneProduct4327 (Entrez Gene)
MMP20GeneProduct9313 (Entrez Gene)
MMP21GeneProduct118856 (Entrez Gene)
MMP23BGeneProduct8510 (Entrez Gene)
MMP24GeneProduct10893 (Entrez Gene)
MMP2GeneProduct4313 (Entrez Gene)
MMP25GeneProduct64386 (Entrez Gene)
MMP27GeneProduct64066 (Entrez Gene)
MMP28GeneProduct79148 (Entrez Gene)
MMP3GeneProduct4314 (Entrez Gene)
MMP7GeneProduct4316 (Entrez Gene)
MMP8GeneProduct4317 (Entrez Gene)
MMP9GeneProduct4318 (Entrez Gene)
MicroangiopathyPathway
NADHMetaboliteQ26987453 (Wikidata)
NADPH oxidaseProteinQ97651124 (Wikidata)
NADPHMetaboliteQ26841327 (Wikidata)
NADPMetaboliteQ26987754 (Wikidata)
NADMetaboliteQ12499775 (Wikidata)
NMDAProteinIPR018882 (InterPro) "increasing N-Methyl-D-Aspartate receptor (NMDAR) phosphorylation reduces its endogenous blockade by magnesium, thereby enhancing calcium (Ca+2) and sodium (Na+) influx" [PMID: 30766472]. Receptor exist in 8 variants.
NOMetabolite16480 (ChEBI)
NRSMetaboliteProbably Nitrate reductases (NRs); in publication [PMID: 30766472] mentioned as "iNOS-NO-NRS axis, activated microglia are a major source of free radicals in the spinal cords of animals with DPN"; might need to be captured as a Protein, EC code: 1.7.99.4
Na+MetaboliteQ31541104 (Wikidata)
Nav1.6ProteinENSG00000196876 (Ensembl)
Nav1.7ProteinENSG00000169432 (Ensembl)
Nav1.8ProteinENSG00000185313 (Ensembl)
Na⁺/K⁺-ATPaseProtein7.2.2.13 (Enzyme Nomenclature) aka sodium–potassium pump
O2- radicalMetabolite61073 (ChEBI)
PGE2MetaboliteQ416554 (Wikidata)
PKCProtein
PKCProtein2.7.11.13 (Enzyme Nomenclature) Assumed to represent Protein kinase C, a family of protein kinases.
PRKCAGeneProduct5578 (Entrez Gene)
PRKCBGeneProduct5579 (Entrez Gene)
PRKCDGeneProduct5580 (Entrez Gene)
PRKCEGeneProduct5581 (Entrez Gene)
PRKCGGeneProduct5582 (Entrez Gene)
PRKCHGeneProduct5583 (Entrez Gene)
PRKCIGeneProduct5584 (Entrez Gene)
PRKCQGeneProduct5588 (Entrez Gene)
PRKCZGeneProduct5590 (Entrez Gene)
PRKD3GeneProduct23683 (Entrez Gene)
Protein KinasesProtein
Protein SynthesisPathway
RAGEProtein177 (Entrez Gene) Also AGER
ROSMetabolite26523 (ChEBI)
SNAP ProteinsProtein
SNAP25GeneProduct6616 (Entrez Gene)
Sensitization HyperexcitationPathway
SorbitolMetaboliteQ245280 (Wikidata)
TKRProteinENSG00000007350 (Ensembl) Also known as TKTL1
TRPA1ProteinO75762 (Uniprot-TrEMBL) AKA transient receptor potential ankyrin-1
TRPV1ProteinQ8NER1 (Uniprot-TrEMBL) AKA transient receptor potential vannilloid-1
Urea CyclePathwayWP4595 (WikiPathways)
cytokinesProteinQ212354 (Wikidata)
e-Metabolite10545 (ChEBI)
glucoseMetaboliteQ37525 (Wikidata)
ion imbalance

Annotated Interactions

No annotated interactions

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