QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, August 17, 2005, 25(33):7601-7614; doi:10.1523/JNEUROSCI.1776-05.2005

This Article Full Text Full Text (PDF) Supplemental data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (38) Citing Articles via Google Scholar Google Scholar Articles by Brigadski, T. Articles by Lessmann, V. Search for Related Content PubMed PubMed Citation Articles by Brigadski, T. Articles by Lessmann, V.

 Previous Article  |  Next Article 

Development/Plasticity/Repair
Differential Vesicular Targeting and Time Course of Synaptic Secretion of the Mammalian Neurotrophins

Tanja Brigadski,¹ Matthias Hartmann,^1,2 and Volkmar Lessmann¹

¹Institute of Physiology and Pathophysiology, Johannes Gutenberg-University, 55128 Mainz, Germany, and ²Department of Molecular Neurobiochemistry, Ruhr-University, 44780 Bochum, Germany

Neurotrophins are a family of secreted neuronal survival and plasticity factors comprising NGF, BDNF, neurotrophin-3 (NT-3), and NT-4. Whereas synaptic secretion of BDNF has been described, the routes of intracellular targeting and secretion of NGF, NT-3, and NT-4 in neurons are poorly understood.

To allow for a direct comparison of intracellular targeting and release properties, all four mammalian neurotrophins were expressed as green fluorescent protein fusion proteins in cultured rat hippocampal neurons. We show that BDNF and NT-3 are targeted more efficiently to dendritic secretory granules of the regulated pathway of secretion (BDNF, in 98% of cells; NT-3, 85%) than NGF (46%) and NT-4 (23%). For all NTs, the remaining cells showed targeting to the constitutive secretory pathway. Fusing the BDNF pre-pro sequence to NT-4 directed NT-4 more efficiently to the regulated pathway of secretion.

All neurotrophins, once directed to the regulated secretion pathway, were detected near synapsin I-positive presynaptic terminals and colocalized with PSD-95-DsRed (postsynaptic density-95-Discosoma red), suggesting postsynaptic targeting of the neurotrophins to glutamatergic synapses. Depolarization-induced release of all neurotrophins from synaptic secretory granules was slow (delay in onset, 10-30 s; = 120-307 s) compared with transmitter release kinetics monitored with FM4-64 [N-(3-triethylammoniumpropyl)-4-(6-(4-diethylamino)phenyl)hexatrienyl)pyridinium dibromide] destaining (onset, <5 s; = 13 ± 2 s). Among the neurotrophins, NT-4 secretion was most rapid but still proceeded 10 times more slowly than transmitter secretion. Preincubation of neurons with monensin (neutralizing intragranular pH, thus solubilizing the peptide core) increased the speed of secretion of BDNF, NGF, and NT-3 to the value of NT-4. These data suggest that peptide core dissolution in secretory granules is the critical determinant of the speed of synaptic secretion of all mammalian NTs and that the speed of release is not compatible with fast transmitter-like actions of neurotrophins.

Key words: NGF; NT-3; NT-4; BDNF; release; PSD-95; VAMP; FM4-64; peptide; secretion; neurotrophins

---

Received July 23, 2004; revised June 24, 2005; accepted June 29, 2005.

This article has been cited by other articles:

				J. de Wit, R. F. Toonen, and M. Verhage Matrix-Dependent Local Retention of Secretory Vesicle Cargo in Cortical Neurons J. Neurosci., January 7, 2009; 29(1): 23 - 37. [Abstract] [Full Text] [PDF]

				X. Xia, V. Lessmann, and T. F. J. Martin Imaging of evoked dense-core-vesicle exocytosis in hippocampal neurons reveals long latencies and kiss-and-run fusion events J. Cell Sci., January 1, 2009; 122(1): 75 - 82. [Abstract] [Full Text] [PDF]

				E. K. de Jong, J. Vinet, V. S. Stanulovic, M. Meijer, E. Wesseling, K. Sjollema, H. W. G. M. Boddeke, and K. Biber Expression, transport, and axonal sorting of neuronal CCL21 in large dense-core vesicles FASEB J, December 1, 2008; 22(12): 4136 - 4145. [Abstract] [Full Text] [PDF]

				G. Leng and M. Ludwig Neurotransmitters and peptides: whispered secrets and public announcements J. Physiol., December 1, 2008; 586(23): 5625 - 5632. [Abstract] [Full Text] [PDF]

				K. L. Lynch, R. R.L. Gerona, D. M. Kielar, S. Martens, H. T. McMahon, and T. F.J. Martin Synaptotagmin-1 Utilizes Membrane Bending and SNARE Binding to Drive Fusion Pore Expansion Mol. Biol. Cell, December 1, 2008; 19(12): 5093 - 5103. [Abstract] [Full Text] [PDF]

				N. Kuczewski, A. Langlois, H. Fiorentino, S. Bonnet, T. Marissal, D. Diabira, N. Ferrand, C. Porcher, and J.-L. Gaiarsa Spontaneous glutamatergic activity induces a BDNF-dependent potentiation of GABAergic synapses in the newborn rat hippocampus J. Physiol., November 1, 2008; 586(21): 5119 - 5128. [Abstract] [Full Text] [PDF]

				N. Kuczewski, C. Porcher, N. Ferrand, H. Fiorentino, C. Pellegrino, R. Kolarow, V. Lessmann, I. Medina, and J.-L. Gaiarsa Backpropagating Action Potentials Trigger Dendritic Release of BDNF during Spontaneous Network Activity J. Neurosci., July 2, 2008; 28(27): 7013 - 7023. [Abstract] [Full Text] [PDF]

				Y. Ben-Ari, J.-L. Gaiarsa, R. Tyzio, and R. Khazipov GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations Physiol Rev, October 1, 2007; 87(4): 1215 - 1284. [Abstract] [Full Text] [PDF]

				R. Kolarow, T. Brigadski, and V. Lessmann Postsynaptic Secretion of BDNF and NT-3 from Hippocampal Neurons Depends on Calcium Calmodulin Kinase II Signaling and Proceeds via Delayed Fusion Pore Opening J. Neurosci., September 26, 2007; 27(39): 10350 - 10364. [Abstract] [Full Text] [PDF]

				E. N. Ottem, L. A. Beck, C. L. Jordan, and S. M. Breedlove Androgen-Dependent Regulation of Brain-Derived Neurotrophic Factor and Tyrosine Kinase B in the Sexually Dimorphic Spinal Nucleus of the Bulbocavernosus Endocrinology, August 1, 2007; 148(8): 3655 - 3665. [Abstract] [Full Text] [PDF]

				M. D. Amaral and L. Pozzo-Miller TRPC3 Channels Are Necessary for Brain-Derived Neurotrophic Factor to Activate a Nonselective Cationic Current and to Induce Dendritic Spine Formation J. Neurosci., May 9, 2007; 27(19): 5179 - 5189. [Abstract] [Full Text] [PDF]

				B. A. Scalettar How Neurosecretory Vesicles Release Their Cargo Neuroscientist, April 1, 2006; 12(2): 164 - 176. [Abstract] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help