Subcellular Localization of Rat Brain Insulin Binding Sites

Marks, Jonathan L.; Maddison, Jill; Eastman, Creswell J

doi:10.1111/j.1471-4159.1988.tb02981.x

Cited by 26 publications

(10 citation statements)

References 40 publications

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“…3). As previously found in adult ani mals, the highest insulin binding was on membranes from olfactory bulb > cerebral cortex = cerebellum > brainstem [11]. However at DO, binding on olfactory bulb = cerebral cortex = hindbrain > cerebellum.…”

Section: Resultssupporting

confidence: 49%

“…The cerebral cortex was isolated by remov ing the diencephalon, the brainstem was defined rostrally at the cerebral peduncle and caudally at Cl and the cerebellum and olfactory bulbs were removed at their connections to the brainstem and cerebral cortex, respec tively. Preparation of crude mitochondrial (P2) and plasma membranes from pooled brain regions was as previously described [11], except that for plasma mem branes from D0-D9 brain regions, the hypotonically lysed P2 fraction was layered over 32.5% (w/w) sucrose instead of over 25% sucrose/32.5% sucrose, followed by the same procedures. Prepared membranes were diluted in excess 5.0 m M Hepes, pH 7.4, centrifuged, diluted to approximately 3.0 mg protein/ml and stored at -10°C for up to 4 weeks prior to use.…”

Section: Methodsmentioning

confidence: 99%

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Ontogeny of Insulin Binding in Different Regions of the Rat Brain

Marks

Eastman²

1990

Dev Neurosci

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Insulin binding was measured on crude mitochondrial or plasma membranes prepared from different rat brain regions during postnatal development. In the cerebral cortex and brainstem, insulin binding decreased 60–70% between birth and the adult period. In the cerebellum, insulin binding doubled in the first 10 postnatal days and then decreased 40% in the adult, while in the olfactory bulb, insulin binding changed little during postnatal development. Postnatal reductions of insulin binding in cerebral cortex and brainstem were from a loss of binding sites and not from a change in binding affinity. Of the major postnatal developmental processes, maximal insulin binding was most closely associated with neuronogenesis, less closely with gliogenesis and not with synaptogenesis, neural process formation or myelination.

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Section: Resultssupporting

confidence: 49%

Section: Methodsmentioning

confidence: 99%

Ontogeny of Insulin Binding in Different Regions of the Rat Brain

Marks

Eastman²

1990

Dev Neurosci

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“…Brain insulin receptors are present in particularly high concentrations in neurons, and in much lower levels in glia (5). Although the mRNA of insulin receptors is largely localized in neuronal somata, abundant insulin receptors are found in both cell bodies and synapses (5)(6)(7). However, very little is known about the functional significance of synaptic insulin receptors in the neurons.…”

mentioning

confidence: 98%

Insulin Stimulates Postsynaptic Density-95 Protein Translation via the Phosphoinositide 3-Kinase-Akt-Mammalian Target of Rapamycin Signaling Pathway

Lee

Huang²,

Wu³

et al. 2005

Journal of Biological Chemistry

172

116

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Insulin receptors are highly enriched at neuronal synapses, but whose function remains unclear. Here we present evidence that brief incubations of rat hippocampal slices with insulin resulted in an increased protein expression of dendritic scaffolding protein postsynaptic density-95 (PSD-95) in area CA1. This insulin-induced increase in the PSD-95 protein expression was inhibited by the tyrosine kinase inhibitor, AG1024, phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and wortmannin, translational inhibitors, anisomycin and rapamycin, but not by LY303511 (an inactive analogue of LY294002), and transcriptional inhibitor, actinomycin D, suggesting that insulin regulates the translation of PSD-95 by activating the receptor tyrosine kinase-PI3K-mammalian target of rapamycin (mTOR) signaling pathway. A similar insulin-induced increase in the PSD-95 protein expression was detected after stimulation of the synaptic fractions isolated from the hippocampal neurons. Furthermore, insulin treatment did not affect the PSD-95 mRNA levels. In agreement, insulin rapidly induced the phosphorylation of 3-phosphoinositidedependent protein kinase-1 (PDK1), protein kinase B (Akt), and mTOR, effects that were prevented by the AG1024 and LY294002. We also show that insulin stimulated the phosphorylation of 4E-binding protein 1 (4E-BP1) and p70S6 kinase (p70S6K) in a mTOR-dependent manner. Finally, we demonstrate the constitutive expression of PSD-95 mRNA in the synaptic fractions isolated from hippocampal neurons. Taken together, these findings suggest that activation of the PI3K-Akt-mTOR signaling pathway is essential for the insulin-induced up-regulation of local PSD-95 protein synthesis in neuronal dendrites and indicate a new molecular mechanism that may contribute to the modulation of synaptic function by insulin in hippocampal area CA1.Insulin and its receptor are widely dispersed throughout the brain with the highest density located in the olfactory bulb, cerebral cortex, hypothalamus, and hippocampus, where they are thought to subserve a number of functions including regulation of glucose metabolism, food intake and body weight, fertility and reproduction, learning, memory, and attention (1-4). Brain insulin receptors are present in particularly high concentrations in neurons, and in much lower levels in glia (5). Although the mRNA of insulin receptors is largely localized in neuronal somata, abundant insulin receptors are found in both cell bodies and synapses (5-7). However, very little is known about the functional significance of synaptic insulin receptors in the neurons. Recently, several studies have drawn links between insulin signaling and intracellular trafficking and plasma membrane expression of ion channels and neurotransmitter receptors at the central nervous system synapses. For example, it has been shown that insulin rapidly recruits functional GABA A receptors to postsynaptic domains in hippocampal neurons, resulting in a long-lasting enhancement of GABA A receptor-mediated synaptic transmission (8). ...

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“…These tyrosine kinase receptors are enriched in neurons and found in cell bodies and nerve terminal membranes of neurons in hypothalamic and higher limbic regions (Marks et al, 1988;Schulingkamp et al, 2000). Accordingly, insulin not only acts at hypothalamic sites as regulator of energy homeostasis in the periphery, but may also modulate cognitive performance and motivation (Kern et al, 2001;Zhao and Alkon, 2001;Figlewicz and Benoit, 2009).…”

Section: Introductionmentioning

confidence: 99%

Insulin Modulates Cocaine-Sensitive Monoamine Transporter Function and Impulsive Behavior

et al. 2011

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Because insulin acutely enhances the function of dopamine transporters, the tyrosine kinase receptors activated by this hormone may modulate transporter-dependent neurochemical and behavioral effects of psychoactive drugs. In this respect, we examined the effects of insulin on exocytotic monoamine release and the efficacy of the monoamine transporter blocker cocaine in rat nucleus accumbens. Whereas insulin reduced electrically evoked exocytotic [ 3 H]dopamine release in nucleus accumbens slices, the hormone potentiated the release-enhancing effect of cocaine thereon. The phosphatidylinositol 3-kinase inhibitor LY294002 abolished these effects, indicating the involvement of insulin receptors. Similar insulin effects were observed on the release of [ 3 H]norepinephrine in nucleus accumbens slices, but not on that of [ 3 H]serotonin, and were also apparent in medial prefrontal cortex slices. As might then be expected, insulin also potentiated the dopamine and norepinephrine release-enhancing effects of the selective monoamine uptake inhibitors GBR12909 and desmethylimipramine, respectively. In subsequent behavioral experiments, we investigated the role of insulin in motor impulsivity that depends on monoamine neurotransmission in the nucleus accumbens. Intracranial administration of insulin in the nucleus accumbens alone reduced premature responses in the five-choice serial reaction time task and enhanced the stimulatory effect of peripheral cocaine administration on impulsivity, resembling the observed neurochemical effects of the hormone. In contrast, cocaine-induced locomotor activity remained unchanged by intra-accumbal insulin application. These data reveal that insulin presynaptically regulates cocainesensitive monoamine transporter function in the nucleus accumbens and, as a consequence, impulsivity. Therefore, insulin signaling proteins may represent targets for the treatment of inhibitory control deficits such as addictive behaviors.

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Subcellular Localization of Rat Brain Insulin Binding Sites

Cited by 26 publications

References 40 publications

Ontogeny of Insulin Binding in Different Regions of the Rat Brain

Ontogeny of Insulin Binding in Different Regions of the Rat Brain

Insulin Stimulates Postsynaptic Density-95 Protein Translation via the Phosphoinositide 3-Kinase-Akt-Mammalian Target of Rapamycin Signaling Pathway

Insulin Modulates Cocaine-Sensitive Monoamine Transporter Function and Impulsive Behavior

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