The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses

The synapse is the primary locus of cell-cell communication in the nervous system. It is now clear that the synapse incorporates diverse cell signalin g modalities in addition to classical neurotransmission. Here we show that two components of the insulin pathway are localized at CNS synapses, where they are components of the postsynaptic density (PSD). An immunochemical sc reen revealed that polypeptides of 58 and 53 kDa (p58/53) were highly enric hed in PSD fractions from rat cerebral cortex, hippocampus, and cerebellum. These polypeptides were purified and microsequenced, revealing that p58/53 is identical to the insulin receptor tyrosine kinase substrate p58/53 (IRS p53). Our analysis of IRSp58/53 mRNA suggests that within rat brain there i s one coding region for IRSp58 and IRSp53; we find no evidence of alternati ve splicing. We demonstrate that IRSp58/53 is expressed in the synapse-rich molecular layer of the cerebellum and is highly concentrated at the synaps es of cultured hippocampal neurons, where it colocalizes with the insulin r eceptor. Together, these data suggest that insulin signaling may play a rol e at CNS synapses.