Editing Brain-derived neurotrophic factor (section)

== Expression ==

The BDNF protein is encoded by a gene that is also called BDNF, found in humans on chromosome 11.<ref name="pmid2236018" /><ref name="pmid1889806" /> Structurally, BDNF transcription is controlled by eight different [[Promoter (genetics)|promoters]], each leading to different [[Transcription (biology)|transcripts]] containing one of eight untranslated 5' [[exons]] (I to VIII) [[RNA splicing|spliced]] to the 3' encoding exon.  Promoter IV activity, leading to the translation of exon IV-containing mRNA, is strongly stimulated by calcium and is primarily under the control of a [[CAMP response element|Cre]] regulatory component, suggesting a putative role for the transcription factor [[CREB]] and the source of BDNF's activity-dependent effects .<ref name="Zheng_2009">{{cite journal | vauthors = Zheng F, Wang H | title = NMDA-mediated and self-induced bdnf exon IV transcriptions are differentially regulated in cultured cortical neurons | journal = Neurochemistry International | volume = 54 | issue = 5–6 | pages = 385–92 | year = 2009 | pmid = 19418634 | pmc = 2722960 | doi = 10.1016/j.neuint.2009.01.006 }}</ref>
There are multiple mechanisms through neuronal activity that can increase BDNF exon IV specific expression.<ref name="Zheng_2009"/>  Stimulus-mediated neuronal excitation can lead to [[NMDA receptor]] activation, triggering a calcium influx.  Through a protein signaling cascade requiring [[Extracellular signal-regulated kinases|Erk]], [[Ca2+/calmodulin-dependent protein kinase II|CaM KII/IV]], [[PI3K]], and [[Phospholipase C|PLC]], NMDA receptor activation is capable of triggering BDNF exon IV transcription. BDNF exon IV expression also seems capable of further stimulating its own expression through TrkB activation.  BDNF is released from the post-synaptic membrane in an activity-dependent manner, allowing it to act on local TrkB receptors and mediate effects that can lead to signaling cascades also involving Erk and CaM KII/IV.<ref name="Zheng_2009"/><ref name="pmid20232397">{{cite journal | vauthors = Kuzumaki N, Ikegami D, Tamura R, Hareyama N, Imai S, Narita M, Torigoe K, Niikura K, Takeshima H, Ando T, Igarashi K, Kanno J, Ushijima T, Suzuki T, Narita M | title = Hippocampal epigenetic modification at the brain-derived neurotrophic factor gene induced by an enriched environment | journal = Hippocampus | volume = 21 | issue = 2 | pages = 127–32 | date = February 2011 | pmid = 20232397 | doi = 10.1002/hipo.20775 | s2cid = 205912003 | doi-access = free }}</ref>  Both of these pathways probably involve calcium-mediated phosphorylation of CREB at Ser133, thus allowing it to interact with BDNF's Cre regulatory domain and upregulate transcription.<ref name="pmid9581763">{{cite journal | vauthors = Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME | title = Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism | journal = Neuron | volume = 20 | issue = 4 | pages = 709–26 | date = April 1998 | pmid = 9581763 | doi = 10.1016/s0896-6273(00)81010-7 | s2cid = 770523 | doi-access = free }}</ref>  However, NMDA-mediated receptor signaling is probably necessary to trigger the upregulation of BDNF exon IV expression because normally CREB interaction with CRE and the subsequent translation of the BDNF transcript is blocked by of the [[basic helix–loop–helix]] transcription factor protein 2 ([[BHLHB2]]).<ref name="Jiang_2008">{{cite journal | vauthors = Jiang X, Tian F, Du Y, Copeland NG, Jenkins NA, Tessarollo L, Wu X, Pan H, Hu XZ, Xu K, Kenney H, Egan SE, Turley H, Harris AL, Marini AM, Lipsky RH | title = BHLHB2 controls Bdnf promoter 4 activity and neuronal excitability | journal = The Journal of Neuroscience | volume = 28 | issue = 5 | pages = 1118–30 | date = January 2008 | pmid = 18234890 | pmc = 6671398 | doi = 10.1523/JNEUROSCI.2262-07.2008 }}</ref>  NMDA receptor activation triggers the release of the regulatory inhibitor, allowing for BDNF exon IV upregulation to take place in response to the activity-initiated calcium influx.<ref name="Jiang_2008"/> Activation of [[Dopamine receptor D5|dopamine receptor D<sub>5</sub>]] also promotes expression of BDNF in [[prefrontal cortex]] neurons.<ref>{{cite journal | vauthors = Perreault ML, Jones-Tabah J, O'Dowd BF, George SR | title = A physiological role for the dopamine D5 receptor as a regulator of BDNF and Akt signalling in rodent prefrontal cortex | journal = The International Journal of Neuropsychopharmacology | volume = 16 | issue = 2 | pages = 477–83 | date = March 2013 | pmid = 22827965 | pmc = 3802523 | doi = 10.1017/S1461145712000685 }}</ref>