Essential Role fordlgin Synaptic Clustering of Shaker K+ChannelsIn Vivo

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Abstract
The assemblage of specific ion channels and receptors at synaptic sites is crucial for signaling between pre- and postsynaptic cells. However, the mechanisms by which proteins are targeted to and clustered at synapses are poorly understood. Here we show that the product of theDrosophila discs-largegene, DLG, is colocalized with Shaker K+channels, which are clustered at glutamatergic synapses at the larval neuromuscular junction. In heterologous cells, DLG can cluster Shaker-type K+channels, and, in the yeast two-hybrid system, the DLG PDZ1–2 domains bind directly to the C-terminal tail of Shaker proteins. We also demonstrate that DLG-Shaker interactions are requiredin vivofor Shaker clustering at the neuromuscular junction. Synaptic clustering of Shaker channels is abolished not only by mutations indlgbut also by a mutation inShakerthat deletes its C-terminal DLG binding motif. Analyses of variousdlgmutant alleles suggest that channel clustering and synaptic targeting functions depend on distinct DLG domains. These studies demonstrate for the first time that DLG plays an important role in synaptic organizationin vivothat correlates with its ability to bind directly to specific membrane proteins of the synapse.