 |
The Journal of Neuroscience, April 19, 2006, 26(16):4256-4265; doi:10.1523/JNEUROSCI.1253-05.2006
 Previous Article | Next Article 
Cellular/Molecular
Structure Function and Splice Site Analysis of the Synaptogenic Activity of the Neurexin-1 LNS Domain
Ethan R. Graf,1
Yunhee Kang,1,2,3
Anna M. Hauner,1 and
Ann Marie Craig1,2
1Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, 2Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada V6T 2B5, and 3Department of Anatomy and Division of Brain Korea 21 Biomedical Science, Korea University College of Medicine, Seoul, South Korea
Correspondence should be addressed to Ann Marie Craig, Brain Research Centre, University of British Columbia Hospital F149, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5. Email: amcraig{at}interchange.ubc.ca
Recent findings suggest that the neurexin-neuroligin link promotes both GABAergic and glutamatergic synaptogenesis, but the mechanism by which neurexins influence the clustering of appropriate neuroligins and postsynaptic differentiation remains unclear. Previous studies suggested that the presence or absence of alternatively spliced residues at splice site 4 (S4) in the neurexin LNS domain may regulate neurexin function. We demonstrate that addition of the S4 insert selectively reduces the ability of neurexin-1 to cluster neuroligin-1/3/4 and glutamatergic postsynaptic proteins, although clustering of neuroligin-2 and GABAergic postsynaptic proteins remain strong. Furthermore, addition of the S4 insert decreases the binding affinity of neurexin-1 to neuroligins-1 and -4 but has little effect on binding to neuroligins-2 and -3. Additional structure-function studies reveal the neurexin binding interface mediating synaptogenic activity to be composed primarily of residues in the 23, 67, and 1011 loops on one rim of the LNS domain sandwich. Mutation of two predicted Ca2+-binding residues disrupts postsynaptic protein clustering and binding to neuroligins, consistent with previous findings that neurexin-neuroligin binding is Ca2+ dependent. Glutamatergic postsynaptic clustering was more readily disrupted by the mutagenesis than GABAergic postsynaptic protein clustering. Perhaps neurexins-neuroligins, or neurexin-1 at least, is most important for GABA synapse formation or controlling the balance of GABA and glutamate synapses. These results suggest that differential neurexin-neuroligin binding affinities and splice variations may play an instructive role in postsynaptic differentiation.
Key words: synaptogenesis; neuroligin; glutamate; GABA; gephyrin; PSD-95; postsynaptic
Received March 31, 2005;
revised March 13, 2006;
accepted March 14, 2006.
Correspondence should be addressed to Ann Marie Craig, Brain Research Centre, University of British Columbia Hospital F149, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5. Email: amcraig{at}interchange.ubc.ca
This article has been cited by other articles:
|
|
|
|
 
A. T. Suckow, D. Comoletti, M. A. Waldrop, M. Mosedale, S. Egodage, P. Taylor, and S. D. Chessler
Expression of Neurexin, Neuroligin, and Their Cytoplasmic Binding Partners in the Pancreatic {beta}-Cells and the Involvement of Neuroligin in Insulin Secretion
Endocrinology,
December 1, 2008;
149(12):
6006 - 6017.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Krivosheya, L. Tapia, J. N. Levinson, K. Huang, Y. Kang, R. Hines, A. K. Ting, A. M. Craig, L. Mei, S. X. Bamji, et al.
ErbB4-Neuregulin Signaling Modulates Synapse Development and Dendritic Arborization through Distinct Mechanisms
J. Biol. Chem.,
November 21, 2008;
283(47):
32944 - 32956.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Reissner, M. Klose, R. Fairless, and M. Missler
Mutational analysis of the neurexin/neuroligin complex reveals essential and regulatory components
PNAS,
September 30, 2008;
105(39):
15124 - 15129.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Patrizi, B. Scelfo, L. Viltono, F. Briatore, M. Fukaya, M. Watanabe, P. Strata, F. Varoqueaux, N. Brose, J.-M. Fritschy, et al.
Synapse formation and clustering of neuroligin-2 in the absence of GABAA receptors
PNAS,
September 2, 2008;
105(35):
13151 - 13156.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Hines, L. Wu, D. J. Hines, H. Steenland, S. Mansour, R. Dahlhaus, R. R. Singaraja, X. Cao, E. Sammler, S. G. Hormuzdi, et al.
Synaptic Imbalance, Stereotypies, and Impaired Social Interactions in Mice with Altered Neuroligin 2 Expression
J. Neurosci.,
June 11, 2008;
28(24):
6055 - 6067.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Koehnke, X. Jin, E. C. Budreck, S. Posy, P. Scheiffele, B. Honig, and L. Shapiro
Crystal structure of the extracellular cholinesterase-like domain from neuroligin-2
PNAS,
February 12, 2008;
105(6):
1873 - 1878.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Kang, X. Zhang, F. Dobie, H. Wu, and A. M. Craig
Induction of GABAergic Postsynaptic Differentiation by {alpha}-Neurexins
J. Biol. Chem.,
January 25, 2008;
283(4):
2323 - 2334.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Flatscher-Bader, N. Zuvela, N. Landis, and P.A. Wilce
Smoking and alcoholism target genes associated with plasticity and glutamate transmission in the human ventral tegmental area
Hum. Mol. Genet.,
January 1, 2008;
17(1):
38 - 51.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Hishimoto, Q.-R. Liu, T. Drgon, O. Pletnikova, D. Walther, X.-G. Zhu, J. C. Troncoso, and G. R. Uhl
Neurexin 3 polymorphisms are associated with alcohol dependence and altered expression of specific isoforms
Hum. Mol. Genet.,
December 1, 2007;
16(23):
2880 - 2891.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. I. Fogel, M. R. Akins, A. J. Krupp, M. Stagi, V. Stein, and T. Biederer
SynCAMs Organize Synapses through Heterophilic Adhesion
J. Neurosci.,
November 14, 2007;
27(46):
12516 - 12530.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Lardi-Studler and J.-M. Fritschy
Matching of Pre- and Postsynaptic Specializations during Synaptogenesis
Neuroscientist,
April 1, 2007;
13(2):
115 - 126.
[Abstract]
[PDF]
|
|
|
|
|
|
|
H. Taniguchi, L. Gollan, F. G. Scholl, V. Mahadomrongkul, E. Dobler, N. Limthong, M. Peck, C. Aoki, and P. Scheiffele
Silencing of Neuroligin Function by Postsynaptic Neurexins
J. Neurosci.,
March 14, 2007;
27(11):
2815 - 2824.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
