INSULIN-RECEPTOR SUBSTRATE-1 (IRS-1) DISTRIBUTION IN THE RAT CENTRAL-NERVOUS-SYSTEM

Insulin receptor substrate 1 (IRS-1) is the primary cytosolic substrat e of the insulin and insulin-like growth factor-I (IGF-I) receptors. F ollowing tyrosine phosphorylation IRS-I binds to and activates specifi c proteins containing SH2 domains. Using biochemical and immunocytoche mical techniques, we have mapped the distribution of IRS-1 in the CNS of the adult rat and compared it with that of insulin and IGF-I recept ors and phosphatidylinositol 3-kinase (PI-3 kinase), a signaling molec ule functionally related to IRS-1. Immunoprecipitation and Western blo tting experiments demonstrate the presence of substantial amounts of I RS-1, insulin receptor, and PI-3 kinase in the brain. IRS-1 immunoreac tivity is widely distributed in neurons from several areas of the brai n and spinal cord. The cerebral cortex, the hippocampus, many hypothal amic and thalamic nuclei, the basal ganglia, the cerebellar cortex, th e brainstem nuclei, and the lamina X of the spinal cord are particular ly rich of immunopositive nerve cells. In these areas most of the neur ons immunoreactive for IRS-1 are also stained by either anti-insulin r eceptor or anti-IGF-I receptor antibodies as well as PI-3 kinase antis erum. IRS-1 immunostaining was very weak or totally absent in neurons of the olfactory bulb, the supraoptic and paraventricular nuclei, the mesencephalic trigeminal nucleus, and the granule cell layer of the ce rebellum, despite the fact that these areas were immunolabeled with an tibodies against insulin or IGF-I receptors and/or PI-3 kinase. These results show that neurons in the adult rat CNS are endowed with some o f the components of the early signaling pathway for growth factors of the insulin/IGF-I family, although IRS-1 has a distribution distinct f rom that of the two receptors.