SHANK2 (SH3 and Multiple Ankyrin Repeat Domain Protein 2), also called CortBP1 and ProSAP1, is a member for the SHANK/ProSAP family of master scaffold proteins. Human SHANK2 is 1470 amino acids (aa) in length with a predicted molecular weight of 158 kDa. It contains an Nâterminal SH3 domain (aa 147â206), one PDZ domain (aa 247â341), a Prolineârich region (PRR; aa 509â535), and a Câterminal SAM domain (aa 1407â1470). SHANK2 is highly expressed in the brain, specifically in the cortex, striatum, hippocampus, olfactory bulb, and Purkinje cells of the cerebellum. In neurons, it functions as a molecular scaffold in the postsynaptic density of excitatory synapses and is essential for dendritic spine formation and enlargement. SHANK2 interacts with more than 30 synaptic proteins including cytoskeletal proteins and glutamate receptors. NMDA receptors link to the SHANK2 PDZ domain via SAPAP proteins, AMPA receptors bind to SHANK2 via the interaction of PSD-95 with Stargazin, an AMPA receptor-associated protein, and metabotropic glutamate receptors are linked to SHANK2 through Homer proteins that bind to its PRR. Mutations of SHANK genes have been associated with autism spectrum disorders and other neurodevelopmental and neuropsychiatric disorders, such as intellectual disability and schizophrenia. SHANK2 is also expressed in epithelial cells in the kidney and liver where it regulates the trafficking and activity of the Na+/H+ Exchanger 3.