Адам ағзасындағы BDNF ақуызы

Protein found in humans

Brain derived neurotrophic factor (BDNF), or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor (NGF), a family which also includes NT 3 and NT 4/NT 5. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves Alain Barde and Hans Thoenen. BDNF activates the TrkB tyrosine kinase receptor.

BDNF acts on certain neurons of the central nervous system and the peripheral nervous system expressing TrkB, helping to support survival of existing neurons, and encouraging growth and differentiation of new neurons and synapses. In the brain it is active in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking. BDNF is also expressed in the retina, kidneys, prostate, motor neurons, and skeletal muscle, and is also found in saliva. BDNF itself is important for long term memory. Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells in a process known as neurogenesis. Neurotrophins are proteins that help to stimulate and control neurogenesis, BDNF being one of the most active. Mice born without the ability to make BDNF have developmental defects in the brain and sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal neural development. Other important neurotrophins structurally related to BDNF include NT 3, NT 4, and NGF. BDNF is made in the endoplasmic reticulum and secreted from dense core vesicles. It binds carboxypeptidase E (CPE), and disruption of this binding has been proposed to cause the loss of sorting BDNF into dense core vesicles. The phenotype for BDNF knockout mice can be severe, including postnatal lethality. Other traits include sensory neuron losses that affect coordination, balance, hearing, taste, and breathing. Knockout mice also exhibit cerebellar abnormalities and an increase in the number of sympathetic neurons. Certain types of physical exercise have been shown to markedly (threefold) increase BDNF synthesis in the human brain, a phenomenon which is partly responsible for exercise induced neurogenesis and improvements in cognitive function. Niacin appears to upregulate BDNF and tropomyosin receptor kinase B (TrkB) expression as well.

BDNF binds at least two receptors on the surface of cells that are capable of responding to this growth factor, TrkB (pronounced "Track B") It may also modulate the activity of various neurotransmitter receptors, including the Alpha 7 nicotinic receptor. BDNF has also been shown to interact with the reelin signaling chain. The expression of reelin by Cajal–Retzius cells goes down during development under the influence of BDNF. The latter also decreases reelin expression in neuronal culture.

The TrkB receptor is encoded by the NTRK2 gene and is member of a receptor family of tyrosine kinases that includes TrkA and TrkC. TrkB autophosphorylation is dependent upon its ligand specific association with BDNF, When the p75 receptor is activated, it leads to activation of NFkB receptor.

The BDNF protein is encoded by a gene that is also called BDNF, found in humans on chromosome 11. There are multiple mechanisms through neuronal activity that can increase BDNF exon IV specific expression. 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. 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). 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.

BDNF has several known single nucleotide polymorphisms (SNP), including, but not limited to, rs6265, C270T, rs7103411, rs2030324, rs2203877, rs2049045 and rs7124442. As of 2008, rs6265 is the most investigated SNP of the BDNF gene

A common SNP in the BDNF gene is rs6265. This point mutation in the coding sequence, a guanine to adenine switch at position 196, results in an amino acid switch: valine to methionine exchange at codon 66, Val66Met, which is in the prodomain of BDNF. The Val66Met mutation results in a reduction of hippocampal tissue and has since been reported in a high number of individuals with learning and memory disorders, major depression, and neurodegenerative diseases such as Alzheimer's and Parkinson's. A meta analysis indicates that the BDNF Val66Met variant is not associated with serum BDNF.

Glutamate is the brain's major excitatory neurotransmitter and its release can trigger the depolarization of postsynaptic neurons. AMPA and NMDA receptors are two ionotropic glutamate receptors involved in glutamatergic neurotransmission and essential to learning and memory via long term potentiation. While AMPA receptor activation leads to depolarization via sodium influx, NMDA receptor activation by rapid successive firing allows calcium influx in addition to sodium. The calcium influx triggered through NMDA receptors can lead to expression of BDNF, as well as other genes thought to be involved in LTP, dendritogenesis, and synaptic stabilization.

NMDA receptor activation is essential to producing the activity dependent molecular changes involved in the formation of new memories. Following exposure to an enriched environment, BDNF and NR1 phosphorylation levels are upregulated simultaneously, probably because BDNF is capable of phosphorylating NR1 subunits, in addition to its many other effects. One of the primary ways BDNF can modulate NMDA receptor activity is through phosphorylation and activation of the NMDA receptor one subunit, particularly at the PKC Ser 897 site. Once activated, Fyn can bind to NR2B through its SH2 domain and mediate phosphorylation of its Tyr 1472 site. Similar studies have suggested Fyn is also capable of activating NR2A although this was not found in the hippocampus. Thus, BDNF can increase NMDA receptor activity through Fyn activation. This has been shown to be important for processes such as spatial memory in the hippocampus, demonstrating the therapeutic and functional relevance of BDNF mediated NMDA receptor activation. It was previously mentioned that AMPA receptor expression is essential to learning and memory formation, as these are the components of the synapse that will communicate regularly and maintain the synapse structure and function long after the initial activation of NMDA channels. BDNF is capable of increasing the mRNA expression of GluR1 and GluR2 through its interaction with the TrkB receptor and promoting the synaptic localization of GluR1 via PKC and CaMKII mediated Ser 831 phosphorylation. It also appears that BDNF is able to influence Gl1 activity through its effects on NMDA receptor activity. BDNF significantly enhanced the activation of GluR1 through phosphorylation of tyrosine830, an effect that was abolished in either the presence of a specific NR2B antagonist or a trk receptor tyrosine kinase inhibitor. While glutamate is the brain's major excitatory neurotransmitter and phosphorylation normally activates receptors, GABA is the brain's primary inhibitory neurotransmitter and phosphorylation of GABAA receptors tend to reduce their activity. Blockading BDNF signaling with a tyrosine kinase inhibitor or a PKC inhibitor in wild type mice produced significant reductions in spontaneous action potential frequencies that were mediated by an increase in the amplitude of GABAergic inhibitory postsynaptic currents (IPSC).

BDNF also enhances synaptogenesis. Synaptogenesis is dependent upon the assembly of new synapses and the disassembly of old synapses by β adducin. Adducins are membrane skeletal proteins that cap the growing ends of actin filaments and promote their association with spectrin, another cytoskeletal protein, to create stable and integrated cytoskeletal networks. Actins have a variety of roles in synaptic functioning. In pre synaptic neurons, actins are involved in synaptic vesicle recruitment and vesicle recovery following neurotransmitter release. In post synaptic neurons they can influence dendritic spine formation and retraction as well as AMPA receptor insertion and removal. PSD 95 localizes the actin remodeling GTPases, Rac and Rho, to synapses through the binding of its PDZ domain to kalirin, increasing the number and size of spines. Thus, BDNF induced trafficking of PSD 95 to dendrites stimulates actin remodeling and causes dendritic growth in response to BDNF.

Laboratory studies indicate that BDNF may play a role in neurogenesis. BDNF can promote protective pathways and inhibit damaging pathways in the NSCs and NPCs that contribute to the brain's neurogenic response by enhancing cell survival. This becomes especially evident following suppression of TrkB activity. Some studies suggest that BDNF may promote neuronal differentiation.

Preliminary research has focused on the possible links between BDNF and clinical conditions, such as depression, schizophrenia, and Alzheimer's disease.

Preliminary studies have assessed a possible relationship between schizophrenia and BDNF. It has been shown that BDNF mRNA levels are decreased in cortical layers IV and V of the dorsolateral prefrontal cortex of schizophrenic patients, an area associated with working memory.

The neurotrophic hypothesis of depression states that depression is associated with a decrease in the levels of BDNF.