synaptic vesicles, the structures and functions of sev- 
eral other synaptic proteins are being studied in Dr. 
Siidhof s laboratory, in particular rab3A and synap- 
sins. Together these studies should contribute to the 
understanding of the molecular basis for nerve ter- 
minal function. 
In a different approach. Dr. Siidhof and his col- 
leagues have studied the receptor for a-latrotoxin, a 
presynaptic spider toxin that causes massive neuro- 
transmitter release from vertebrate nerve terminals. 
Purification of the receptor revealed it to be com- 
posed of a family of related high-molecular-weight 
subunits ranging from 160,000 to 220,000 and a 
low-molecular-weight component of 29,000. 
Cloning of these polypeptides demonstrated that 
the low-molecular-weight component represents a 
secreted protein with no sequence homology to 
current entries in the data banks. 
The high-molecular-weight components, on the 
other hand, were discovered to be members of a poly- 
morphic family of brain-specific cell surface receptors 
called neurexins. At least three genes for neurexins 
exist, each of which contains two independent pro- 
moters that specify transcripts whose coding region 
differs by more than 1 ,000 amino acids. Extensive al- 
ternative splicing creates a multitude of neurexins 
whose number could exceed 200 different proteins. 
Sequence analysis demonstrated that the neurexins 
contain a repeated sequence motif homologous to re- 
peats found in several extracellular matrix proteins, in 
particular laminin A, agrin, slit, and perlecan. Most of 
these proteins have a well-characterized function in 
neuronal development and interact with cell surfaces, 
suggesting that the motif may represent a cell adhe- 
sion domain and that the neurexins may be cell adhe- 
sion receptors. The polymorphic nature of the neur- 
exins together with the synaptic localization of at least 
some of them led Dr. Siidhof and his colleagues to 
propose that they may represent synaptic cell recogni- 
tion molecules involved in establishing synaptic speci- 
ficity. A grant from the Perot Family Foundation pro- 
vided support for the project described above. 
A surprising result of the purification of the a- 
latrotoxin receptor was that a synaptic vesicle mem- 
brane protein, synaptotagmin, copurified with it. 
The suggestion raised by this observation, namely 
that the receptor might directly interact with synap- 
totagmin, was confirmed with affinity chromatogra- 
phy and other biochemical assays. Furthermore, 
when the cytoplasmic domains of different neurex- 
ins were tested for their ability to interact with syn- 
aptotagmin, they were also found to bind in a se- 
quence-specific manner. These results suggest that 
synaptotagmins may target synaptic vesicles specifi- 
cally to the active zone by interactions with the a- 
latrotoxin receptor and other neurexins, which 
would confer specificity to the otherwise nonspe- 
cific interactions of synaptotagmin with the phos- 
pholipid bilayer. 
In work that is primarily funded by the National 
Institute of Mental Health, Dr. Siidhofs laboratory 
has also investigated the role of inositol 1,4,5-tris- 
phosphate (InsPj) receptors in regulating intracel- 
lular Ca^^ concentrations in neurons. Neurons con- 
tain particularly high levels of InsP, receptors, and 
Dr. Siidhofs laboratory discovered and molecularly 
cloned several novel InsPj receptors. In addition, 
structure-function relationships in InsP3 receptors 
were explored, leading to the characterization of 
the ligand-binding domain in multiple InsPj recep- 
tors and to an elucidation of how Ca^^ regulates 
InsPj binding and InsP3 receptor function. These 
studies will further the understanding of the dy- 
namics of intracellular Ca^^ in neurons. 
Dr. Siidhof is also Professor of Molecular Genet- 
ics at the University of Texas Southwestern Medi- 
cal Center at Dallas. 
Articles 
Brose, N., Petrenko, A.G., Siidhof, T.C., and Jahn, 
R. 1992. Synaptotagmin: a calcium sensor on the 
synaptic vesicle surface. Science 256:1021- 
1025. 
Cameron, P.L., Siidhof, T.C., Jahn, R., and De Ca- 
milli, P. 1991. Colocalization of synaptophysin 
with transferrin receptors: implications for synap- 
tic vesicle biogenesis. / Ce// Biol 1 15:151-164. 
Lin, H.C., Siidhof, T.C., and Anderson, R.G.W. 
1992. Annexin VI is required for budding of 
clathrin-coated pits. Cell 70:283-291. 
Matteoli, M., Takei, K., Cameron, R., Hurlbut, P., 
Johnston, P. A., Siidhof, T.C., Jahn, R., and De 
Camilli, P. 1991 . Association of rab3A with syn- 
aptic vesicles at late stages of the secretory path- 
way. / Ce// fi/o/ 115:625-633. 
Matteoli, M., Takei, K., Perin, M.S., Siidhof, T.C., 
and DeCamilli, P. 1992. Exo-endocytotic recy- 
cling of synaptic vesicles in developing processes 
of cultured hippocampal neurons. / Cell Biol 
117:849-861. 
Mignery, G.A., Johnston, P.A., and Siidhof, T.C. 
1992. Mechanism of Ca^"^ inhibition of inositol 
1,4,5-trisphosphate (InsP,) binding to the cere- 
bellar InsPj receptor. / Biol Chem 261 -.l 450- 
7455. 
Petrenko, A.G., Perin, M.S., Davletov, B.A., Ush- 
karyov, Y.A., Geppert, M., and Siidhof, T.C. 
1991. Binding of synaptotagmin to the a-latro- 
NEUROSCIENCE 445 
