Update articleMechanisms, locations, and kinetics of synaptic BDNF secretion: An update
Introduction
Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3, and neurotrophin-4 (NT-3, NT-4) constitute the protein family of mammalian neurotrophins. They are secreted homodimeric proteins (monomeric size of mature neurotrophins: 119–129 amino acids; molecular weight: approximately 14 kDa) which are synthesized and released from neurons as well as from innervated non-neuronal tissues (i.e., muscles). Neurotrophins are well-known for their supporting action in regulating neuronal development, differentiation, and survival of distinct neuronal populations (Lewin and Barde, 1996). In addition, especially BDNF is known since long to be a crucial mediator of synaptic plasticity in the central nervous system, both, during development and in the adult. Numerous pre- and postsynaptic actions of BDNF have been described for GABAergic as well as glutamatergic synaptic transmission (for recent reviews see e.g., Carvalho et al., 2008, Lu et al., 2008, Bramham and Messaoudi, 2005; Gottmann et al., in press). Many of these synaptic phenomena have been revealed either after unrestricted and chronic (i.e. long-term) depletion of endogenous BDNF, e.g., in BDNF knockout animals, or following equally unrestricted delivery of additional exogenous BDNF to specific brain areas, acute brain slices, or cultured neurons. However, within the last few years it emerged that understanding the mechanisms of BDNF secretion at the subcellular level, and monitoring the synaptic input specific actions of secreted BDNF is of fundamental importance to uncover the role of BDNF in synaptic plasticity in more detail. In this respect it is no longer doubted that BDNF can be secreted from pre- and postsynaptic structures (Kohara et al., 2001, Kojima et al., 2001, Hartmann et al., 2001; for a recent review see Lessmann et al., 2003), leading to spatially restricted synaptic actions of BDNF (Magby et al., 2006, Walz et al., 2006, Amaral and Pozzo-Miller, 2007b, Lang et al., 2007, Tanaka et al., 2008). Whereas these effects have been attributed mainly to the mature form of BDNF (i.e., the fully processed homodimeric protein, with pre- and prodomains cleaved off), increasing evidence suggests that also the precursor, the so-called proBDNF, can be released and may exert distinctly different biological actions than the mature counterpart. However, no matter whether neurotrophins are secreted as pro-versions or as mature proteins, exocytosis of these proteins can take place either via activity-dependent exocytosis from excitable cells bearing secretory granules, or via the constitutive release pathway, which is present in all cell types. The current update article attempts to summarize the recent progress in the fields of cellular synthesis, prodomain cleavage, subcellular targeting, and synaptic secretion of BDNF and other neurotrophins in neurons, and discusses the consequences of these findings for shaping synaptic plasticity. Further, this article will distinguish between axonal (presynaptic) and dendritic (postsynaptic) release of neurotrophins which likely serve different cellular effects and almost certainly employ differential molecular mechanisms of secretion. We will focus mainly on data obtained from CNS neurons rather than from cell lines, because previous studies suggested that – when it goes to important details – targeting and secretion in cell lines may differ from the respective processes in neurons (Lessmann et al., 2003).
Section snippets
Synthesis, cleavage, and targeting of BDNF and other neurotrophins in central neurons
NTs, like other neuropeptides, are synthesized as pre-proproteins into the ER. The pre-domain is cleaved off immediately, yielding so-called proproteins which can undergo further posttranslational modifications on their way through Golgi apparatus and trans-Golgi network (TGN), to finally end up in secretory vesicles. Two separate types of secretion pathways exist: (i) the regulated pathway, employing Ca2+-dependent exocytosis of secretory granules, and (ii) the constitutive pathway, which
The role of proBDNF and other proneurotrophins
As mentioned in Section 2.1, concepts assuming that pro-domains are just an extension to guide sorting and targeting of mature NTs can no longer be judged valid. Thus, this chapter will consider the targeting, secretion, and possible functions of proneurotrophins.
Location of BDNF secretion: targeting to axons and dendrites
For a better understanding of the role of BDNF in synaptic plasticity, the question arises where in the cell BDNF release can take place. Because of the low level of BDNF expression in most neuronal tissues, unequivocal evidence regarding the subcellular localization of the small amounts of endogenous BDNF in neuronal processes is still lacking. Consequently, the question whether endogenously expressed BDNF is preferentially located in axons or dendrites, or whether release of endogenous BDNF
Acknowledgements
This work was funded by grants to V.L. from the DFG (SFB 779 TP B6, LE 1020/2-1), the Schram Stiftung, and the Stiftung Rheinland-Pfalz für Innovation.
References (115)
- et al.
Neurotrophin trafficking by anterograde transport
Trends Neurosci.
(1998) - et al.
Delay between fusion pore opening and peptide release from large dense-core vesicles in neuroendocrine cells
Neuron
(2002) - et al.
N-terminal processing: the methionine aminopeptidase and N alpha-acetyl transferase families
Trends Biochem. Sci.
(1998) - et al.
BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis
Prog. Neurobiol.
(2005) - et al.
Brain-derived neurotrophic factor regulates the expression and synaptic delivery of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunits in hippocampal neurons
J. Biol. Chem.
(2007) - et al.
The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function
Cell
(2003) - et al.
The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer's disease
Mol. Cell Neurosci.
(2001) - et al.
Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules
Cell
(2004) - et al.
Frequency-dependent kinetics and prevalence of kiss-and-run and reuse at hippocampal synapses studied with novel quenching methods
Neuron
(2006) - et al.
The regulated secretion and vectorial targeting of neurotrophins in neuroendocrine and epithelial cells
J. Biol. Chem.
(1996)
Neurotrophin-4, alone or heterodimerized with brain-derived neurotrophic factor, is sorted to the constitutive secretory pathway
J. Biol. Chem.
Comparative biology of Ca2+-dependent exocytosis: implications of kinetic diversity for secretory function
Trends Neurosci.
Proprotein convertases in tumor progression and malignancy: novel targets in cancer therapy
Am. J. Pathol.
Early patterns of electrical activity in the developing cerebral cortex of humans and rodents
Trends Neurosci.
Neurotrophin secretion: current facts and future prospects
Prog. Neurobiol.
Proteolytic processing of proNGF is necessary for mature NGF regulated secretion from neurons
Biochem. Biophys. Res. Commun.
Sorting and activity-dependent secretion of BDNF require interaction of a specific motif with the sorting receptor carboxypeptidase e
Neuron
BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory?
Neurobiol. Learn. Mem.
Costorage and coexistence of neuropeptides in the mammalian CNS
Prog. Neurobiol.
Essential role for TrkB receptors in hippocampus-mediated learning
Neuron
Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor
J. Biol. Chem.
Pro-region of neurotrophins determines the processing efficiency
Biochem. Biophys. Res. Commun.
A bi-directional carboxypeptidase E-driven transport mechanism controls BDNF vesicle homeostasis in hippocampal neurons
Mol. Cell Neurosci.
Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase
Neuron
Furin-mediated proprotein processing activity: involvement of negatively charged amino acid residues in the substrate binding region
Biochimie
Activity-dependent expression of brain-derived neurotrophic factor in dendrites: facts and open questions
Neurosci. Res.
Difference in trafficking of brain-derived neurotrophic factor between axons and dendrites of cortical neurons, revealed by live-cell imaging
BMC Neurosci.
Induction of long-term potentiation and depression is reflected by corresponding changes in secretion of endogenous brain-derived neurotrophic factor
Proc. Natl. Acad. Sci. U.S.A.
BDNF induces calcium elevations associated with IBDNF, a nonselective cationic current mediated by TRPC channels
J. Neurophysiol.
TRPC3 channels are necessary for brain-derived neurotrophic factor to activate a nonselective cationic current and to induce dendritic spine formation
J. Neurosci.
Regulation of dense core release from neuroendocrine cells revealed by imaging single exocytic events
Nat. Neurosci.
Differential properties of GTP- and Ca(2+)-stimulated exocytosis from large dense core vesicles
Traffic
Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons
J. Neurosci.
Neurotrophin-evoked depolarization requires the sodium channel Na(V)1.9
Nature
Differential vesicular targeting and time course of synaptic secretion of the mammalian neurotrophins
J. Neurosci.
Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade
Proc. Natl. Acad. Sci. U.S.A.
Secretory granule exocytosis
Physiol. Rev.
Role of the brain-derived neurotrophic factor at glutamatergic synapses
Br. J. Pharmacol.
Milieu-induced, selective aggregation of regulated secretory proteins in the trans-Golgi network
J. Cell Biol.
What the granins tell us about the formation of secretory granules in neuroendocrine cells
Cell Biophys.
Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons
J. Neurosci.
Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway
J. Neurosci.
Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport
J. Neurosci.
BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain
Nature
BDNF modulation of NMDA receptors is activity dependent
J. Neurophysiol.
Localization of brain-derived neurotrophic factor to distinct terminals of mossy fiber axons implies regulation of both excitation and feedforward inhibition of CA3 pyramidal cells
J. Neurosci.
NMDA receptors induce somatodendritic secretion in hypothalamic neurones of lactating female rats
J. Physiol.
Mutant huntingtin impairs the post-Golgi trafficking of brain-derived neurotrophic factor but not its Val66Met polymorphism
J. Neurosci.
Vesicular trafficking of semaphorin 3A is activity-dependent and differs between axons and dendrites
Traffic
Peptides other than the neurotrophins that can be cleaved from proneurotrophins: a neglected story
Arch. Physiol. Biochem.
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