CRC 629 B11 - Intracellular trafficking and signaling of the synaptic organizer molecules neurexins

Basic data for this project

Description

Synapses are intercellular junctions in which cell adhesion molecules connect the presynaptic machinery for neurotransmitter release to the postsynaptic machinery for receptor signaling. Neurotransmitter release requires the presynaptic co-assembly of Ca2+-channels with the secretory apparatus, but little is known about how these components are organized. α-Neurexins, a highly-polymorph family of cell-surface proteins encoded by three genes (NRXN1-3), link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ-domain proteins. Using multiple knockout mice, we have shown that α-neurexins are essential for Ca2+-triggered neurotransmitter release from excitatory and inhibitory synapses, and of secretory granules from (neuro-)endocrine cells. Although the regulation of release by α-neurexins may involve an impaired Ca2+-channel function, the exact mechanisms have remained elusive. In preliminary work for this grant proposal, we observed that different protein motifs of the intracellular C-terminus of neurexins may be critically important for the targeting to synapses, and that the cytoactive matrix component Rim1 may constitute a novel interaction partner via its PDZ-domain. Both neurexins and Rim proteins may be responsible for anchoring Ca2+-channels in the vicinity of fusion-ready vesicles. Based on these observations, we should address the following aspects in our current project: Characterization of the intracellular trafficking of neurexins from the start of expression to the insertion at the synapse, including the identity of the presumed transport vesicles and the dynamics of their targeting. Analysis of the molecular determinants of the transport process, including the newly proposed interaction with Rim proteins. Subsynaptic localization of neurexins and Ca2+ channels, including the role of their supramolecular complex for the establishment of Ca2+ microdomains. Thereby, our work program will contribute to the question how cell-adhesion molecules such as a-neurexins organize synapses by functionally coupling Ca2+-channels to the presynaptic machinery.