Insulin receptor substrate-1 (IRS-1) distribution in the rat central nervous system

Abstract

Insulin receptor substrate 1 (IRS-1) is the primary cytosolic substrate of the insulin and insulin-like growth factor-I (IGF-I) receptors. Following tyrosine phosphorylation IRS-1 binds to and activates specific proteins containing SH2 domains. Using biochemical and immunocytochemical 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 receptors and phosphatidylinositol 3-kinase (PI-3 kinase), a signaling molecule functionally related to IRS-1. Immunoprecipitation and Western blotting experiments demonstrate the presence of substantial amounts of IRS-1, insulin receptor, and PI-3 kinase in the brain. IRS-1 immunoreactivity is widely distributed in neurons from several areas of the brain and spinal cord. The cerebral cortex, the hippocampus, many hypothalamic and thalamic nuclei, the basal ganglia, the cerebellar cortex, the brainstem nuclei, and the lamina X of the spinal cord are particularly rich of immunopositive nerve cells. In these areas most of the neurons immunoreactive for IRS-1 are also stained by either anti-insulin receptor or anti-IGF-I receptor antibodies as well as PI-3 kinase antiserum. 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 cerebellum, despite the fact that these areas were immunolabeled with antibodies 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 of the components of the early signaling pathway for growth factors of the insulin/IGF-I family, although IRS-1 has a distribution distinct from that of the two receptors.

Insulin-Like Growth Factor-1 Inhibits Adult Supraoptic Neurons via Complementary Modulation of Mechanoreceptors and Glycine Receptors

“…Our present findings further support a possible major neuromodulatory role of IGF-1 in the adult mammalian nervous system. Both IGF-1 receptor and IGF-1 are present within the SON of adult rats A maintained expression of IGF-1 receptors in adult rat SON neurons has been reported previously (Folli et al, 1994;CardonaGomez et al, 2000). We confirmed this and further showed that this receptor is present on the soma and dendrites of both OT and VP neurons, providing morphological support to our functional results.…”

“…These two mechanisms act in concert to finely modulate neuronal activity Voisin and Bourque, 2002). IGF-1 immunoreactivity and mRNA have been observed in adult SON neurons (Aguado et al, 1992;Zhou et al, 1999), and high expression of the IGF-1 receptor has been reported in the SON (Folli et al, 1994;Cardona-Gomez et al, 2000).…”

Effects of Sex and Insulin/Insulin-Like Growth Factor-1 Signaling on Performance in an Associative Learning Paradigm inCaenorhabditis elegans

“…Lesions to the hippocampus produce severe loss of learning ability and memory that can be significantly reversed by insulin treatment (De Castro and Balagura 1976;Horel 1978;Huppert and Piercy 1979;Spiers et al 2001). Both insulin receptor substrate-1 and phosphatidyinositol-3 phosphate kinase are abundantly expressed in the rat hippocampus (Folli et al 1994). The PI3K inhibitor LY294002 blocks learning and memory in mice (Barros et al 2001;Lin et al 2001).…”

The Neuroanatomical Axis for Control of Energy Balance

“…Insulin receptors have also been identified in the DVC and a number of other caudal brainstem sites (e.g., 189,193). Like hypothalamic neurons bearing insulin receptors, those in the brainstem also are endowed with intracellular signaling substrates including insulin receptor substrate-1 and phosphatidylinositol 3-kinase (61). The consequences of brainstem insulin signaling to intake and body weight control have yet to be explored by 4th-icv or brainstem intraparenchymal administration studies.…”