We thus propose that Ca2+ triggers release in a two-stage reaction

that involves a close collaboration between synaptotagmin and complexin. Prior to Ca2+ influx, both synaptotagmin and complexin interact with the fusion machinery composed of a partly assembled SNARE/SM protein complex to activate the complex and enable a fast BI 2536 cell line response to Ca2+. Such interaction is indicated by the “clamping” activity of synaptotagmin and complexin and by the priming activity of complexin. When Ca2+ levels rise during an action potential, Ca2+ binding to synaptotagmin triggers a rearrangement of the overall fusion complex containing also complexin and synaptotagmin, such that part of complexin is displaced from the complex via the Ca2+-dependent SNARE complex interaction of synaptotagmin, and the SNARE complex is moved with respect to the membrane via the Ca2+-dependent phospholipid interaction of synaptotagmin. This overall proposal is consistent with the available data but far from proven—no direct evidence for an upstream activity of synaptotagmin apart from its clamping activity is available, and the atomic basis of the various interactions has not been elucidated. Given the detailed current understanding of how a presynaptic terminal converts a presynaptic action potential into a

transsynaptic SAR405838 clinical trial neurotransmitter signal, and how the terminal not only translates an action potential into neurotransmitter release but also computes the action potential signal dependent on the previous use of a synapse and on extrinsic inputs—given this detailed understanding, is there anything left to be done? This question is particularly pertinent because of current views that the molecular and computational mechanisms of synaptic transmission do not matter for an understanding of the brain and that not only synapses but even entire neurons can be dealt with as unitary STK38 entities in the large information-processing machine that constitutes

the brain. At present, a widely shared opinion is that understanding the architecture of the brain will be sufficient for explaining how the brain works, maybe combined with a description about information flow, similar to the beautiful drawings of Cajal that have dominated neuroscientists’ vision for a century. However, understanding the brain is not like understanding a house where features like air ducts, electrical connections, and window locks are just details that you do not really need to know in order to live in it. Instead of one house, a brain is rather like an assembly of billions of houses—the synapses—each of which has their own air ducts, electrical connections, and window locks.