CASK is a recently identified cytosolic protein kinase with homology to the Ca2+/CaM-dependent kinases and the synaptic associated proteins SAPs/PSDs. Like the SAPs, CASK contains a PDZ domain, an SH3 region, and a guanylate kinase domain. However, unlike the rest of the PDZ protein family, the amino terminus of CASK has significant homology with the Ca2+/Calmodulin-dependent kinases. Although widely expressed, CASK is highly enriched in the synaptic plasma membrane where it associates with neurexins, the neuronal cell surface proteins. Neurexins are a complex family of surface proteins that act as receptors for a number of venoms and toxins and regulate the clustering of several ion channels at the synapse. In addition, neurexins bind heterotypically to neuroligins, therefore adjoining different cell types. Neuroligins bind intracellularly to PSD95 and related proteins, whereas neurexins bind to CASK through their C-terminal region and at CASK's PDZ domain. The interaction of neurexins and CASK at the outside of the cell may modulate CASK's activity and trigger an intracellular signaling cascade.