Download How Ca2+ triggers neurotransmitter release

Molecular mechanisms of neurotransmitter release
Thomas C. Südhof
Thomas Südhof's research investigates how neurons in brain communicate with each
other during synaptic transmission, which is the process that underlies all brain activity,
from consciousness over memory to sensory perception and movements. When
stimulated, a presynaptic neuron releases a chemical message – called a
neurotransmitter – that diffuses across the synaptic cleft to stimulate postsynaptic
receptors. Synaptic transmission is initiated with this release of neurotransmitters, and
completed with the postsynaptic response. However, synaptic transmission is more than
just the transfer of information between neurons – synaptic transmission also processes
the transferred information, rendering each synapse a microcomputer that remembers
previous events and that constitutes the minimal information processing unit in brain.
Thomas Südhof began his inquiry into synaptic transmission by focusing on the
presynaptic nerve terminal. When he started, scientists knew that calcium ions stimulate
the release of neurotransmitters from membrane-bound sacs called vesicles into the
synapse, in a process that takes less than a millisecond. But how this worked was
unknown: What allowed rapid neurotransmitter discharge? How did release occur at the
specific region of the neuron—the synapse? How did repeated activity change the
presynaptic neuron? How did the pre- and postsynaptic neurons come together at the
synapse? These are the questions that Thomas Südhof decided to address in his
laboratory.
Among the many discoveries in his laboratory, Südhof revealed how synaptotagmins,
proteins that sense calcium ions and bind to other proteins, facilitate either quick or slow
neurotransmitter release from the presynaptic neuron. Furthermore, his work identified
Munc18-1 and SNARE proteins mediate the fusion of the vesicles with the presynaptic
plasma membrane, the process that effects neurotransmitter release and that is
controlled by synaptotagmins. He also found RIMs and Munc13s—proteins that help
fuse neurotransmitter vesicles to the presynaptic nerve cell membrane and enable the
nerve cell to transmit messages more easily with experience. The work on
synaptotagmin has become a paradigm of how calcium controls membrane traffic that
appears to be universally applicable.
In more recent years, Südhof's work has broadenied to focus on the organization of
synapses in brain, addressing questions of how synapses form, and how the specificity
of synapse formation – the fact that synapses only form between particular neurons and
have characteristic properties – is achieved. Among others, he identified proteins on
presynaptic neurons, called neurexins, and proteins on the postsynaptic neuron, called
neuroligins, that come together and bind at the synapse. There are many types of
neurexins and neuroligins, and the pairing of any two helps create the properties of a
synapse and the wide variability in the types of connections in the brain. Other
molecules contribute to the formation of synapses in a precisely orchestrated ensemble,
creating the living brain as an information processing machine with impressive
capabilities as we know it.
Thomas Südhof has received several recognitions for his work on neurotransmitter
release, including the Wilhelm Feldberg Award, the U.S. National Academy Award in
Molecular Biology (shared with Richard Scheller), the Bernhard Katz Award, Biophysical
Society (shared with Reinhard Jahn), the Passano Foundation Award, the Kavli Award
(shared with James Rothman and Richard Scheller), the Lasker-deBakey Award in
Basic Medical Research (shared with Richard Scheller) and the Nobel Prize in
Physiology or Medicine (shared with James Rothman and Randy Schekman).