Neurotrophins are a family of secreted proteins that regulate development, maintenance and function of vertebrate nervous systems. They act via two different classes of receptor: p75NTR (a member of the TNF receptor superfamily), and neurotrophic tyrosine kinase receptors (NTRKs) - also known as tropomyosin-related kinases (Trks) []. NTRKs are multi-domain, transmembrane proteins - in addition to their cytoplasmic kinase domains, members of the family possess a number of extracellular leucine-rich repeat (LRR) and Ig-like C2-type regions. Ligand binding induces them to dimerise, resulting in activation of their cytoplasmic tyrosine kinase domains. The activated receptors couple to a variety of intracellular signalling cascades, including the Ras, phosphatidylinositol-3-kinase (PI-3 kinase), mitogen-activated protein (MAP) kinase, and phospholipase C (PLC)-gamma pathways []. NTRK1 (also termed TrkA) is a high-affinity receptor for nerve growth factor (NGF). The receptor is expressed in the dorsal root ganglia, trigeminal ganglia and sympathetic neurons of the peripheral nervous system, and in basal forebrain cholinergic neurons []. It is also expressed in peripheral sites, such as scalp skin []. Whereas p75NTR activation by NGF induces apoptosis, NTRK1 mediates the growth factor's cell survival-promoting effects [].
This entry represents the Leucine Rich Repeat C-terminal (LRRCT) capping motif found in growth factor receptors, such as NTRK1 (also known as Trk-A) [].
During the development of the vertebrate nervous system, many neurons become redundant (because they have died, failed to connect to target cells, etc.) and are eliminated. At the same time, developing neurons send out axon outgrowths that contact their target cells []. Such cells control their degree of innervation (the number of axon connections) by the secretion of various specific neurotrophic factors that are essential for neuron survival. One of these is nerve growth factor (NGF), which is involved in the survival of some classes of embryonic neuron (e.g., peripheral sympathetic neurons) []. NGF is mostly found outside the central nervous system (CNS), but slight traces have been detected in adult CNS tissues, although a physiological role for this is unknown []; it has also been found in several snake venoms [, ]. Proteins similar to NGF include brain-derived neurotrophic factor (BDNF) and neurotrophins 3 to 7, all of which demonstrate neuron survival and outgrowth activities. Although NGF was originally identified in snake venom, its most abundant and best studied source is the submaxillary gland of adult male mice []. Mouse NGF is a high molecular weight hexamer, composed of 2 subunits each of alpha, beta and gamma polypeptides. The beta subunit (NGF-beta) is responsible for the physiological activity of the complex []. NGF-beta induces its cell survival effects through activation of neurotrophic tyrosine kinase receptor type 1 (NTRK1; also called TrkA), and can induce cell death by binding to the low affinity nerve growth factor receptor, p75NTR []. The neurotophin has been shown to be involved in sympathetic axon growth and innervation of target fields []. Mammalian NGF-beta tend to be higher potency NTRK1 agonsits than their snake venom counterparts []. In humans, NGF-beta gene mutations can cause a loss of pain perception [].
