mBDNF and proBDNF regulation of GABA neurotransmission (WP4829)

Homo sapiens

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This pathway depicts the regulation of GABA receptor surface expression of BDNF signaling. BDNF can be secreted in both a mature form (mBDNF) and a precursor form (proBDNF), both of which modulate GABA synaptic transmission in neurons. mBDNF activates TrkB receptors leading to an inhibition of GABAAR endocytosis and a consequent increase in cell surface expression of these receptors through the PI 3-kinase and the PKC signaling pathway. In addition, BDNF/TrkB signaling regulates GABAAR and KCC2 at the transcriptional level through the Shc, PLCg and MAP/ERK pathways. proBDNF activates NGFR, which decreases GABAARs cell surface expression through the RhoA/ROCK/PTEN pathway, through dephosphorylation of GABAAR followed by endocytosis and degradation of internalized receptors. proBNDF/NGFR signaling also leads to the transcriptional repression of GABAAR synthesis through JAK2/STAT3/CREM. The proBDNF/NGFR signaling also decreases KCC2 expression. This pathway is based on figure 1 from [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121065/ Porcher et al].

Authors

Kristina Hanspers

Activity

last edited

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Organisms

Homo sapiens

Communities

Annotations

Pathway Ontology

brain-derived neurotrophic factor signaling pathway

Disease Ontology

epilepsy

Participants
Query Drugst.One

Label Type Compact URI Comment
GABRA1 GeneProduct ensembl:ENSG00000022355
PLCG1 GeneProduct ensembl:ENSG00000124181
proBDNF GeneProduct ensembl:ENSG00000176697
RHOA GeneProduct ensembl:ENSG00000067560
AP2A1 GeneProduct ensembl:ENSG00000196961
CREM GeneProduct ensembl:ENSG00000095794
CREB1 GeneProduct ensembl:ENSG00000118260
STAT3 GeneProduct ensembl:ENSG00000168610
SLC12A5 GeneProduct ensembl:ENSG00000124140
NTRK2 GeneProduct ensembl:ENSG00000148053
NGFR GeneProduct ensembl:ENSG00000064300
PTEN GeneProduct ensembl:ENSG00000171862
PIK3CA GeneProduct ensembl:ENSG00000121879
PIK3CB GeneProduct ensembl:ENSG00000051382
PIK3R1 GeneProduct ensembl:ENSG00000145675
PIK3R2 GeneProduct ensembl:ENSG00000105647
PIK3R3 GeneProduct ensembl:ENSG00000117461
PIK3CG GeneProduct ensembl:ENSG00000105851
AP2A2 GeneProduct ensembl:ENSG00000183020
AP2B1 GeneProduct ensembl:ENSG00000006125
SLC12A5 GeneProduct ensembl:ENSG00000124140
mBDNF GeneProduct ensembl:ENSG00000176697
SLC12A5 GeneProduct ensembl:ENSG00000124140
ROCK1 GeneProduct ensembl:ENSG00000067900
JAK2 GeneProduct ensembl:ENSG00000096968 CAV2; caveolin 2
Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:16452
SHC1 GeneProduct ensembl:ENSG00000160691
GABRA2 GeneProduct ensembl:ENSG00000151834
GABRA3 GeneProduct ensembl:ENSG00000011677
GABRA4 GeneProduct ensembl:ENSG00000109158
GABRA5 GeneProduct ensembl:ENSG00000186297
GABRA6 GeneProduct ensembl:ENSG00000145863
GABRB1 GeneProduct ensembl:ENSG00000163288
GABRB2 GeneProduct ensembl:ENSG00000145864
GABRB3 GeneProduct ensembl:ENSG00000166206
GABRG1 GeneProduct ensembl:ENSG00000163285
GABRG2 GeneProduct ensembl:ENSG00000113327
GABRG3 GeneProduct ensembl:ENSG00000182256
GABRD GeneProduct ensembl:ENSG00000187730
GABRE GeneProduct ensembl:ENSG00000102287
GABRP GeneProduct ensembl:ENSG00000094755
GABRQ GeneProduct ensembl:ENSG00000268089

References

  1. Constitutive endocytosis of GABAA receptors by an association with the adaptin AP2 complex modulates inhibitory synaptic currents in hippocampal neurons. Kittler JT, Delmas P, Jovanovic JN, Brown DA, Smart TG, Moss SJ. J Neurosci. 2000 Nov 1;20(21):7972–7. PubMed Europe PMC Scholia
  2. Mechanism of BDNF Modulation in GABAergic Synaptic Transmission in Healthy and Disease Brains. Porcher C, Medina I, Gaiarsa JL. Front Cell Neurosci. 2018 Aug 28;12:273. PubMed Europe PMC Scholia