Involved in maintenance of high-frequency synaptic transmission at hippocampal CA3-CA1 synapses. Regulates AMPA-type glutamate receptor (AMPAR) immobilization at postsynaptic density keeping the channels in an activated state in the presence of glutamate and preventing synaptic depression (PubMed:26931375). May play a role in self-renewal and differentiation of spermatogonial stem cells by inhibiting canonical Wnt signaling pathway (PubMed:28196692). Component of the postsynaptic hippocampal AMPA-type glutamate receptor (AMPAR) complex, at least composed of pore forming AMPAR subunits GRIA1, GRIA2 and GRIA3 and AMPAR auxiliary proteins SHISA6 and SHISA7 (PubMed:26931375, PubMed:29199957). Interacts (via PDZ-binding motif) with DLG4/PSD-95 (via PDZ domain); the interaction is direct (PubMed:26931375). Highly expressed in cerebellum and hippocampal neurons: CA1 stratum oriens and stratum radiatum, CA3 stratum oriens and stratum lucidum, and the dentate gyrus polymorphic layer (PubMed:26931375). Expressed in other brain structures including olfactory bulb, cortex, amygdala and midbrain (at protein level) (PubMed:26623514, PubMed:26931375). Also expressed in a subset of spermatogonial stem cells (PubMed:28196692). Also expressed in eye, heart, kidney, lung, muscle and spleen. Isoform 2: Specifically expressed in hippocampus (PubMed:26931375). Barely detectable in the brain of embryonic day 17 (17 dpc). Expressed in hippocampus and septum from postnatal day 1 (P1) and then in cerebellum and olfactory bulb from postnatal day 7 (P7). The PDZ-binding motif interacts with PDZ-domain of scaffolding protein DLG4. N-glycosylated. Decreases decay times of miniature excitatory postsynaptic currents (mEPSCs) and light-induced AMPA-type glutamate receptor (AMPAR) currents in CA1 pyramidal cell. Belongs to the shisa family.