Chronic hyperglycemia impairment of neuron function (Homo sapiens)

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23MMPNeuronMicroangiopathyFrom gliaExcessiveglucoseGrowthconeLegendAGEPRKCGPRKCINa+BDNFMMP20SorbitolMMP9MMP19MMP3FructoseMMP1NADNADPPRKCQMMP10Sensitization andhyperexcitationPRKCZMMP27MMP12Urea cycleATPDNAMMP23BProteinkinasesSNAP25Glut-1O2- radicalNADHMMP15C3PRKD3TKRNADPHGPCRMMP28MMP2PKCMMP13ETCPRKCDMMP16PRKCEMMP17NADPHoxidasePRKCHMMP11PRKCBCytokinesMMP25ADPNa⁺/K⁺-ATPaseMMP24RAGEMMP7BDNF-TrkBsignalingSorbitol dehydrogenaseMMP21MMP8PGE2TRPV1MMP14PRKCAO2- radical1, 4Glut-3GlucoseGlucoseGlucoseROSProteinsynthesisBlood vesselCa2+K+K+Na+Na+K+IonimbalanceROSe-NONRSINOSAGE1, 4ROSTRPA1NMDANav1.62Nav1.7Nav1.8BDNFRFrom gliaPKCMMPSNAPproteinsSNAPproteinsAldose reductaseNO


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. This pathway diagram corresponds to https://pfocr.wikipathways.org/figures/PMC6365454__fnins-13-00025-g0002.html.

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Quality Tags

Ontology Terms

 

Bibliography

  1. 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
  2. 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
  3. King RH; ''The role of glycation in the pathogenesis of diabetic polyneuropathy.''; Mol Pathol, 2001 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

View all...
CompareRevisionActionTimeUserComment
128337view02:37, 2 February 2024EweitzModified description
128336view12:56, 1 February 2024EweitzBold "Excessive glucose" and "Growth cone", like original diagram
128335view12:47, 1 February 2024EweitzIncrease height of sugar nodes
128334view12:45, 1 February 2024EweitzBold sugar nodes on primary axis, like original diagram
128333view12:43, 1 February 2024EweitzAdd missing nodes: aldose reductase and NO
128332view02:14, 1 February 2024EweitzEconomize layout
128331view02:01, 1 February 2024EweitzEconomize layout
128330view01:44, 1 February 2024EweitzEconomize layout horizontally
128329view01:35, 1 February 2024EweitzPolish graphics
128328view01:30, 1 February 2024EweitzEconomize layout
128327view01:07, 1 February 2024EweitzColor blood vessel, label neuron, refine growth cone color
128326view00:54, 1 February 2024EweitzUse line thickness 2 instead of 3 (site shows much thicker than PathVisio)
128325view00:52, 1 February 2024EweitzRefine graphics per source: color growth cone, thicken some lines
128324view00:36, 1 February 2024EweitzIdentify pathway
128322view00:27, 1 February 2024EweitzClarify glucose reaction, refine microangiopathy to disease node
128321view23:59, 31 January 2024EweitzOntology Term : 'brain small vessel disease' added !
128319view23:12, 31 January 2024EweitzConvert legended-but-unidentified pointers to text
128318view23:02, 31 January 2024EweitzDenote legend
128317view22:55, 31 January 2024EweitzEconomize layout
128316view22:49, 31 January 2024EweitzGroup abstracted genes, refine text placement for readability
128315view22:45, 31 January 2024EweitzStandardize case
126558view09:40, 2 June 2023DdiglesAdded rhea ID
126557view09:19, 2 June 2023DdiglesAdded sorbitol dehydrogenase
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 !

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteQ185253 (Wikidata)
AGEMetabolite84123 (ChEBI)
ATPMetaboliteQ80863 (Wikidata)
Aldose reductaseProtein1.1.1.21 (Enzyme Nomenclature)
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)
CytokinesProteinQ212354 (Wikidata)
DNAPathwayWP466 (WikiPathways)
ETCPathwayWP111 (WikiPathways) Assumed to mean 'Electron Transport Chain'
FructoseMetaboliteQ61738075 (Wikidata)
GPCRProteinQ38173 (Wikidata)
GlucoseMetaboliteQ37525 (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)"
Ion imbalance
K+Metabolite29103 (ChEBI)
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)
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 synthesisPathwayWP1812 (WikiPathways)
RAGEProtein177 (Entrez Gene) Also AGER
ROSMetabolite26523 (ChEBI)
SNAP25GeneProduct6616 (Entrez Gene)
Sensitization and hyperexcitationPathway
Sorbitol dehydrogenaseProteinQ00796 (Uniprot-TrEMBL)
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)
e-Metabolite10545 (ChEBI)

Annotated Interactions

SourceTargetTypeDatabase referenceComment
SorbitolFructosemim-conversion33033 (Rhea)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP5283"
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