TrK Receptor Animation

Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system. Trk receptors affect neuronal survival and differentiation through several signal cascades. However, the activation of these receptors also has significant effects on functional properties of neurons.

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The common ligands of trk receptors are neurotrophins, a family of growth factors critical to the functioning of the nervous system. The binding of these molecules is highly specific. Each type of neurotrophin has different binding affinity toward its corresponding trk receptor. The activation of Trk receptors by neurotrophin binding may lead to activation of signal cascades resulting in promoting survival and other functional regulation of cells.
The abbreviation trk (often pronounced 'track') stands for tropomyosin-receptor-kinase (and not tyrosine kinase nor tropomyosin-related kinase, as has been commonly mistaken).
The family of Trk receptors is named for the oncogene trk, whose identifical led to the discovery of its first member, TrkA. trk, initially identified in a colon carcinoma, is frequently (25%) activated in thyroid papillary carcinomas . The oncogene was generated by a mutation in chromosome 1 that resulted in the fusion of the first seven exons of tropomyosin to the transmembrane and cytoplasmic domains of the then-unknown TrkA receptor . Normal Trk receptors do not contain amino acid or DNA sequences related to tropomyosin.
The three most common types of trk receptors are trkA, trkB, and trkC. Each of these receptors types has different binding affinity to certain types of neurotrophins. The differences in the signaling initiated by these distinct types of receptors are important for generating diverse of biological responses.
Neurotrophin ligands of Trk receptors are processed ligands, meaning that they are synthesized in immature forms and then transformed by protease cleavage. Immature neurotrophins are specific only to one common p75NTR receptor. However, protease cleavage generates neurotrophins that have higher affinity to their corresponding Trk receptors. These processed neurotrophins can still bind to p75NTR, but at a much lower affinity.
TrkA has the highest affinity to the binding nerve growth factor (NGF). NGF is important in both local and nuclear actions, regulating growth cones, motility, and expression of genes encoding the biosynthesis enzymes for neurotransmitters. Nocireceptive sensory neurons express mostly trkA and not trkB or trkC.
TrkB has the highest affinity to the binding brain-derived neurotrophic factor (BDNF) and NT-4. BDNF is growth factor that has important roles in the survival and function of neurons in the central nervous system. The binding of BDNF to TrkB receptor causes many intercellular cascades be activated, which regulate neuronal development and plasticity, long-term potentiation, and apoptosis.
Although both BDNF and NT-4 have high specificity to TrkB, they are not interchangeable. In a mouse model study where BDNF expression was replaced by NT-4, the mouse with NT4 expression appeared to be smaller and exhibited decreased fertility.
Recently, studies have also indicated that TrkB receptor is associated with Alzheimer's disease.
TrkC is ordinarily activated by binding with NT-3 and has little activation by other ligands. (TrkA and TrkB also bind NT-3, but to a lesser extent.) TrkC is mostly expressed by proprioceptive sensory neurons. The axons of these proprioceptive sensory neurons are much thicker than those of nocireceptive sensory neurons, which express trkA.
Essential roles in differentiation and function Precursor cell survival and proliferation
Numerous studies, both in vivo and in vitro, have shown that neurotrophins have proliferation and differentiation effects on CNS neuro-epithelial precursors, neural crest cells, or precursors of the enteric nervous system. TrkA that expresses NGF not only increase the survival of both C and A delta classes of nocireceptor neurons, but also affect the functional properties of these neurons.4 As mentioned before, BDNF improves the survival and function of neurons in CNS, particularly cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex.
BDNF belongs to the neurotrophin family of growth factors and affects the survival and function of neurons in the central nervous system, particularly in brain regions susceptible to degeneration in AD. BDNF improves survival of cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex.
TrkC that expresses NT3 has been shown to promote proliferation and survival of cultured neural crest cells, oligodendrocyte precursors, and differentiation of hippocampal neuron precursors.
Control of target innervation
Each of the neurotrophins mentioned above[vague] promotes neurite outgrowth. NGF/TrkA signaling regulates the advance of sympathetic neuron growth cones; even when neurons received adequate trophic (sustaining and nourishing) support, one experiment showed they did not grow into relating compartments without NGF.[vague] NGF increases the innervation of tissues that receive sympathetic or sensory innervation and induces aberrant innervation in tissues that are normally not innervated.
NGF/TrkA signaling upregulates BDNF, which is transported to both peripheral and central terminals of nocireceptive sensory neurons. In the periphery, TrkB/BDNF binding and TrkB/NT-4 binding acutely sensitizing nocireceptive pathway that require the presence of mast cells.
Sensory neuron function
Trk receptors and their ligands (neurotrophins) also affect neurons' functional properties. Both NT-3 and BDNF are important in the regulation and development of synapses formed between afferent neurons and motor neurons.Increased NT-3/trkC binding results in larger monosynaptic excitatory postsynaptic potentials (EPSPs) and reduced polysynaptic components. On the other hand, increased NT-3 binding to trkB to BDNF[vague] has the opposite effect, reducing the size of monosynaptic excitatory postsynaptic potentials (EPSPs) and increasing polysynaptic signaling.
Formation of ocular dominance column
In the development of mammalian visual system, axons from each eyes crosses through the lateral geniculate nucleus (LGN) and terminate in separate layers of striate cortex. However, axons from each LGN can only be driven by one side of the eye, but not both together. tThese axons that terminate in layer IV of the striate cortex result in ocular dominance columns. A study shows that The density of innervating axons in layer IV from LGN can be increased by exogenous BDNF and reduced by a scavenger of endogenous BDNF. Therefore, it raises the possibility that both of these agents are involved in some sorting mechanism that is not well comprehended yet.Previous studies with cat model has shown that monocular deprivation occurs when input to one of the mammalian eyes is absent during the critical period (critical window). However, A study demonstrated that the infusion of NT-4 (a ligand of trkB) into the visual cortex during the critical period has been shown to prevent many consequences of monocular deprivation.Surprisingly, even after losing responses during the critical period, the infusion of NT-4 has been shown to be able to restore them.

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