Insulin receptors in the brain: structural and physiological characterization. Neurochem Res 13: 297-303
Department of Physiology, University of Florida College of Medicine, Gainesville 32610. Neurochemical Research
(Impact Factor: 2.59).
05/1988; 13(4):297-303. DOI: 10.1007/BF00972477
The present study was conducted to characterize insulin receptors and to determine the effects of insulin in synaptosomes prepared from adult rat brains. Binding of125I-insulin to synaptosome insulin receptors was highly specific and time dependent: equilibrium binding was obtained within 60 minutes, and a t1/2 of dissociation of 26 minutes. Cross-linking of125I-insulin to its receptor followed by SDS-PAGE demonstrated that the apparent molecular weight of the alpha subunit of the receptor was 122,000 compared with 134,000 for the liver insulin receptor. In addition, insulin stimulated the dose-dependent phosphorylation of exogenous tyrosine containing substrate and a 95,000 MW plasma membrane associated protein, in a lectin-purified insulin receptor preparation. The membrane associated protein was determined to be the β subunit of the insulin receptor. Incubation of synaptosomes with insulin caused a dose-dependent inhibition of specific sodium-sensitive [3H]norepinephrine uptake. Insulin inhibition of [3H]norepinephrine uptake was mediated by a decrease in active uptake sites without any effects in theK
m, and was specific for insulin since related and unrelated peptides influenced the uptake in proportion to their structural similarity with insulin. These observations indicate that synaptosomes prepared from the adult rat brain possess specific insulin receptors and insulin has inhibitory effects on norepinephrine uptake in the preparation.
Available from: Acosta C
- "IGF-I itself has been detected in astrocytes and neurons of the central nervous system (CNS) (Garcia-Segura et al. 1991; Garcia-Estrada et al. 1992). The receptors for insulin (IR) and IGF-I (IGFIR) as well as other components of these signaling pathways are expressed throughout the mammalian brain with particularly high concentrations in the hypothalamus, the hippocampus, and the cerebral cortex (Raizada et al. 1988; Unger et al. 1989; Pons 1991 #392). "
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ABSTRACT: The beneficial effects of insulin and insulin-like growth factor I on cognition have been documented in humans and animal
models. Conversely, obesity, hyperinsulinemia, and diabetes increase the risk for neurodegenerative disorders including Alzheimer's
disease (AD). However, the mechanisms by which insulin regulates synaptic plasticity are not well understood. Here, we report
that complete disruption of insulin receptor substrate 2 (Irs2) in mice impairs long-term potentiation (LTP) of synaptic transmission
in the hippocampus. Basal synaptic transmission and paired-pulse facilitation were similar between the 2 groups of mice. Induction
of LTP by high-frequency conditioning tetanus did not activate postsynaptic N-methyl-D-aspartate (NMDA) receptors in hippocampus slices from Irs2−/− mice, although the expression of NR2A, NR2B, and PSD95 was equivalent to wild-type controls. Activation of Fyn, AKT, and
MAPK in response to tetanus stimulation was defective in Irs2−/− mice. Interestingly, IRS2 was phosphorylated during induction of LTP in control mice, revealing a potential new component
of the signaling machinery which modulates synaptic plasticity. Given that IRS2 expression is diminished in Type 2 diabetics
as well as in AD patients, these data may reveal an explanation for the prevalence of cognitive decline in humans with metabolic
disorders by providing a mechanistic link between insulin resistance and impaired synaptic transmission.
Available from: Aurelio Galli
- "However, initial studies of insulin's regulation of the norepinephrine transporter (NET) function were more consistent. For example, insulin inhibits NE uptake in whole brain neuronal cultures, dissociated brain cells, and whole brain synaptosomes (Boyd et al., 1985, 1986; Masters et al., 1987; Raizada et al., 1988). Furthermore, Figlewicz et al. demonstrated that nanomolar concentrations of acute insulin decrease NE uptake from both hypothalamic and hippocampal rat slices (Figlewicz et al., 1993), and that insulin also inhibits NE uptake in PC12 cells which endogenously synthesize NE and express NET (Figlewicz et al., 1993). "
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ABSTRACT: Across species, the brain evolved to respond to natural rewards such as food and sex. These physiological responses are important for survival, reproduction and evolutionary processes. It is no surprise, therefore, that many of the neural circuits and signaling pathways supporting reward processes are conserved from Caenorhabditis elegans to Drosophilae, to rats, monkeys and humans. The central role of dopamine (DA) in encoding reward and in attaching salience to external environmental cues is well recognized. Less widely recognized is the role of reporters of the "internal environment", particularly insulin, in the modulation of reward. Insulin has traditionally been considered an important signaling molecule in regulating energy homeostasis and feeding behavior rather than a major component of neural reward circuits. However, research over recent decades has revealed that DA and insulin systems do not operate in isolation from each other, but instead, work together to orchestrate both the motivation to engage in consummatory behavior and to calibrate the associated level of reward. Insulin signaling has been found to regulate DA neurotransmission and to affect the ability of drugs that target the DA system to exert their neurochemical and behavioral effects. Given that many abused drugs target the DA system, the elucidation of how dopaminergic, as well as other brain reward systems, are regulated by insulin will create opportunities to develop therapies for drug and potentially food addiction. Moreover, a more complete understanding of the relationship between DA neurotransmission and insulin may help to uncover etiological bases for "food addiction" and the growing epidemic of obesity. This review focuses on the role of insulin signaling in regulating DA homeostasis and DA signaling, and the potential impact of impaired insulin signaling in obesity and psychostimulant abuse.
Available from: Heinrich J G Matthies
- "Importantly, previous studies implicate a clear role for insulin, a metabolic hormone, in the regulation of NET function. Indeed, insulin inhibits NE uptake in whole brain neuronal cultures, dissociated brain cells, and whole brain synaptosomes (Boyd et al., 1985; Boyd et al., 1986; Masters et al., 1987; Raizada et al., 1988). Furthermore, Figlewicz et al. demonstrated the ability of nanomolar concentrations of acute insulin to decrease NE uptake from both hypothalamic and hippocampal slices (Figlewicz et al., 1993). "
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ABSTRACT: Noradrenergic signaling in the CNS plays an essential role in circuits involving attention, mood, memory, and stress as well as providing pivotal support for autonomic function in the peripheral nervous system. The high-affinity norepinephrine (NE) transporter (NET) is the primary mechanism by which noradrenergic synaptic transmission is terminated. Data indicate that NET function is regulated by insulin, a hormone critical for the regulation of metabolism. Given the high comorbidity of metabolic disorders such as diabetes and obesity with mental disorders such as depression and schizophrenia, we sought to determine how insulin signaling regulates NET function and thus noradrenergic homeostasis. Here, we show that acute insulin treatment, through the downstream kinase protein kinase B (Akt), significantly decreases NET surface expression in mouse hippocampal slices and superior cervical ganglion neuron boutons (sites of synaptic NE release). In vivo manipulation of insulin/Akt signaling, with streptozotocin, a drug that induces a type 1-like diabetic state in mice, also results in aberrant NET function and NE homeostasis. Notably, we also demonstrate that Akt inhibition or stimulation, independent of insulin, is capable of altering NET surface availability. These data suggest that aberrant states of Akt signaling such as in diabetes and obesity have the potential to alter NET function and noradrenergic tone in the brain. Furthermore, they provide one potential molecular mechanism by which Akt, a candidate gene for mood disorders such as schizophrenia and depression, can impact brain monoamine homeostasis.
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