Neurotrophins are a family of closely related proteins that were identified initially as survival factors for sensory and sympathetic neurons, and have since been shown to control many aspects of survival, development and function of neurons in both the peripheral and the central nervous systems. Each of the four mammalian neurotrophins has been shown to activate one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, each neurotrophin activates p75 neurotrophin receptor (p75NTR), a member of the tumour necrosis factor receptor superfamily. Through Trk receptors, neurotrophins activate Ras, phosphatidyl inositol-3 (PI3)-kinase, phospholipase C-g1 and signalling pathways controlled through these proteins, such as the MAP kinases. Activation of p75NTR results in activation of the nuclear factor-kB (NF-kB) and Jun kinase as well as other signalling pathways. Limiting quantities of neurotrophins during development control the number of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. The neurotrophins also regulate cell fate decisions, axon growth, dendrite growth and pruning and the expression of proteins, such as ion channels, transmitter biosynthetic enzymes and neuropeptide transmitters that are essential for normal neuronal function. Continued presence of the neurotrophins is required in the adult nervous system, where they control synaptic function and plasticity, and sustain neuronal survival, morphology and differentiation. They also have additional, subtler roles outside the nervous system. In recent years, three rare human genetic disorders, which result in deleterious effects on sensory perception, cognition and a variety of behaviours, have been shown to be attributable to mutations in brain-derived neurotrophic factor and two of the Trk receptors.

/pdf/neurotrophin-regulated-signalling-pathways-30f9o18vav.pdf

Neurotrophin-regulated signalling pathways

For decades, astrocytes have been considered to be non-excitable support cells of the brain. However, this view has changed radically during the past twenty years. The recent recognition that they are organized in separate territories and possess active properties — notably a competence for the regulated release of 'gliotransmitters', including glutamate — has enabled us to develop an understanding of previously unknown functions for astrocytes. Today, astrocytes are seen as local communication elements of the brain that can generate various regulatory signals and bridge structures (from neuronal to vascular) and networks that are otherwise disconnected from each other. Examples of their specific and essential roles in normal physiological processes have begun to accumulate, and the number of diseases known to involve defective astrocytes is increasing.

Astrocytes, from brain glue to communication elements: the revolution continues.

Since the purification of BDNF in 1982, a great deal of evidence has mounted for its central roles in brain development, physiology, and pathology. Aside from its importance in neural development and cell survival, BDNF appears essential to molecular mechanisms of synaptic plasticity. Basic activity-related changes in the central nervous system are thought to depend on BDNF modification of synaptic transmission, especially in the hippocampus and neocortex. Pathologic levels of BDNF-dependent synaptic plasticity may contribute to conditions such as epilepsy and chronic pain sensitization, whereas application of the trophic properties of BDNF may lead to novel therapeutic options in neurodegenerative diseases and perhaps even in neuropsychiatric disorders.

Brain-derived Neurotrophic Factor

BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis.

Neurotrophins are growth factors with crucial roles in the developing and mature nervous system. They are initially synthesized as precursor proteins (pro-neurotrophins), which are processed intracellularly to be secreted mostly in a mature, biologically active form (Mowla et al., 1999; Mowla et al., 2001; Matsumoto et al., 2008; for review see Lu et al., 2005). Pro-neurotrophins can also influence developing and mature neural circuits, and may be released in a developmentally regulated manner (Lee et al., 2001; Lu et al., 2005; Teng et al., 2005; Yang et al., 2009). Neurotrophins bind two classes of membrane receptors, the tropomyosin receptor kinase (Trk) family of receptors and the p75 neurotrophin receptor (p75NTR) (for a review see Chao, 2003). The actions of mature neurotrophins are mediated by the high affinity full-length Trk receptors, which signal through their intrinsic tyrosine kinase activity to promote growth. Trk receptors signal by dimerization of receptor molecules, leading to intracellular phosphorylation and activation of intracellular signaling cascades (Ullrich and Schlessinger, 1990; Jing et al., 1992). Truncated Trk receptors (Trk.T) are splice variants of full-length Trks, which lack the intracellular tyrosine kinase domain, and are thought to act as negative effectors of full-length receptors (Luikart et al., 2003), although they may also have their own signaling properties (Rose et al., 2003; Ohira et al., 2006). The neurotrophins show binding specificity for particular Trk receptors: nerve growth factor (NGF) binds to TrkA, brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NT4) to TrkB, and neurotrophin 3 (NT3) to TrkC (Chao, 2003). The p75NTR has low affinity for the mature neurotrophins, but can form a complex with Trk receptors to form high affinity binding sites for neurotrophins, enabling the receptor to participate in the stimulation of growth processes (Esposito et al., 2001). Moreover, p75NTR displays high affinity binding with pro-neurotrophins, and induces apoptosis by interacting with sortilin (Lee et al., 2001; Nykjaer et al., 2004). Thus, pro-neurotrophins and mature neurotrophins may utilize distinct receptors to mediate divergent neuronal actions. This review focuses on the actions of mature BDNF, highlighting the role that BDNF plays in the development of synaptic connectivity in the central nervous system (CNS). Evidence supporting presynaptic actions by target-released BDNF, and the influence that BDNF exerts during the structural development of neurons are reviewed here.

/pdf/brain-derived-neurotrophic-factor-and-the-development-of-476pe0r0nc.pdf

Brain-Derived Neurotrophic Factor and the Development of Structural Neuronal Connectivity

Neurotrophine sind Proteine, die, ähnlich wie Nervenwachstumsfaktoren, die Entwicklung, das Überleben und Funktionieren von Neuronen gewährleisten bzw. fördern (Barde 1989). Dafür binden die Neurotrophine an Rezeptoren in der neuronalen Membran, die zu der Familie der Tyrosin-Rezeptor-Kinasen (Trk) gehören. Christine Rose und weitere Mitglieder der Arbeitsgruppe von Arthur Konnerth vom Physiologischen Institut der LM Universität München haben in ihrem Artikel jetzt eine neue Rolle dieser Proteine beschrieben, und zwar bei dem Dialog wenig von dem vollständigen TrkB-Rezeptor exprimieren, dafür aber um so mehr von dem verkürzten Rezeptor TrkB-T1. BDNF löst in Gliazellen über diesen verkürzten Rezeptor eine Signalkaskade aus, die nicht eine Tyrosinkinase aktiviert (die fehlt ja eben bei diesen Rezeptoren), sondern, wie viele Liganden metabotroper Rezeptoren, an ein G-Protein gekoppelt ist. So konnte erstmals gezeigt werden, dass auch die unvollständigen TrkB-T1-Rezeptoren funktionelle Rezeptoren darstellen, die, zumindest in Gliazellen, eine Signalkaskade in Gang setzen.

Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells

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Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells