Insulin inhibits rat hippocampal neurones via activation of ATP-sensitive K+ and large conductance Ca2+-activated K+ channels

O’Malley, Dervla; Shanley, Lynne; Harvey, Jenni

doi:10.1016/s0028-3908(03)00081-9

Cited by 57 publications

(60 citation statements)

References 40 publications

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“…In this study, spontaneous bursting activity in the cerebral cortical neurons of the El mouse, which shows a high susceptibility to convulsions, was also completely inhibited by IbTX (Jin et al, 2000). However, insulin and leptin that inhibit epileptiform-like bursting activities in rat hippocampal neurons might involve in activation of BK channels (O'Malley et al, 2003;Shanley et al, 2002). Interestingly, BK channel knockout mice do no apparently exhibit seizures but cerebellar-related neurological problems (i.e.…”

Section: Discussionmentioning

confidence: 54%

“…Functionally, a deficit in axonal or presynaptic BK channels might render mossy fibers hyperexcitable during epileptogenesis. Insulin inhibits pyramidal neurons through a similar mechanism that was proposed as a potential therapeutic target for the treatment of epilepsy (O'Malley et al, 2003). Moreover, it was proposed that during periods of enhanced synaptic activity excessive activation of group I and II metabotropic glutamate receptors (mGluR I and II) inhibits the apamin-insensitive slow Ca 2+ -activated K + current in hippocampal CA1 pyramidal neurons that in turn can cause epileptogenesis (Martin et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

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Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

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In the hippocampus, BK channels are preferentially localized in presynaptic glutamatergic terminals including mossy fibers where they are thought to play an important role regulating excessive glutamate release during hyperactive states. Large conductance calcium-activated potassium channels (BK, MaxiK, Slo) have recently been implicated in the pathogenesis of genetic epilepsy. However, the role of BK channels in acquired mesial temporal lobe epilepsy (MTLE) remains unknown. Here we used immunohistochemistry, laser scanning confocal microscopy (LSCM), western immunoblotting and RT-PCR to investigate the expression pattern of the alpha-pore forming subunit of BK channels in the hippocampus and cortex of chronically epileptic rats obtained by the pilocarpine model of MTLE. All epileptic rats experiencing recurrent spontaneous seizures exhibited a significant down-regulation of BK channel immunostaining in the mossy fibers at the hilus and stratum lucidum of the CA3 area. Quantitative analysis of immunofluorescence signals by LSCM revealed a significant 47% reduction in BK channel in epileptic rats when compared to age-matched non-epileptic control rats. These data correlate with a similar reduction in BK channel protein levels and transcripts in the cortex and hippocampus. Our data indicate a seizure-related down-regulation of BK channels in chronically epileptic rats. Further functional assays are necessary to determine whether altered BK channel expression is an acquired channelopathy or a compensatory mechanism affecting the network excitability in MTLE. Moreover, seizure-mediated BK down-regulation may disturb neuronal excitability and presynaptic control at glutamatergic terminals triggering exaggerated glutamate release and seizures.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

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“…Our previous studies have demonstrated that insulin, via activation of BK-and ATP-sensitive K ϩ (K ATP ) channels, potently inhibits the aberrant synaptic activity induced by Mg 2ϩ removal in hippocampal neurons (O'Malley et al, 2003). In this study, we examined the effects of insulin on native and recombinant (hSlo) BK channels expressed in hippocampal and HEK293 cells, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Insulin receptor-driven MAPK stimulation is thought to underlie insulin modulation of hippocampal learning and memory because increases in tyrosine phosphorylation of Shc and MAPK were observed after water maze training (Zhao et al, 1999). We have also shown that insulin inhibits hippocampal epileptiform-like activity via MAPK-driven activation of K ATP and BK channels (O'Malley et al, 2003).…”

mentioning

confidence: 83%

Insulin Activates Native and Recombinant Large Conductance Ca²⁺-Activated Potassium Channels via a Mitogen-Activated Protein Kinase-Dependent Process

O’Malley¹,

Harvey²

2004

Mol Pharmacol

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Evidence is accumulating that, in addition to regulating peripheral energy metabolism, insulin is an important modulator of neuronal function. Indeed, high levels of insulin and insulin receptors are expressed in several brain regions including the hippocampus. We have shown previously that insulin inhibits aberrant synaptic activity in hippocampal neurons via activation of large conductance Ca 2ϩ -activated K ϩ (BK) channels. In this study, we have examined further the effects of insulin on native hippocampal and recombinant (hSlo) BK channels expressed in human embryonic kidney (HEK) 293 cells. Pipette or bath application of insulin evoked a rapid increase in hippocampal BK channel activity, an action caused by activation of insulin receptors because insulin-like growth factor 1 (IGF-1) failed to mimic insulin action. In parallel studies, insulin, applied via the pipette or bath, also activated hSlo channels expressed in HEK293 cells. Although phosphoinositide 3-kinase is a key component of insulin and IGF-1 receptor signaling pathways, activation of this lipid kinase does not underlie the effects of insulin because neither 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) nor wortmannin inhibited or reversed insulin action. However, specific inhibitors of mitogenactivated protein kinase (MAPK) activation, 2Ј-amino-3Ј-methoxyflavone (PD98059) or 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)-butadiene (U0126), attenuated insulin action, indicating that a MAPK-dependent mechanism underlies this process. Furthermore, insulin activation of this pathway enhances BK channel activity by shifting the Ca 2ϩ -sensitivity such that BK channels are active at more hyperpolarized membrane potentials. Because postsynaptic BK channels are important regulators of neuronal hyperexcitability, insulin-induced activation of BK channels, via stimulation of a MAPK-dependent pathway, may be an important process for regulating hippocampal function under normal and pathological conditions.

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“…That insulin and leptin act on the same pool of neurons is further demonstrated by studies showing that both hormones inhibit large conductance calcium-activated potassium channels in a hippocampal slice preparation (58,59). However, leptin's effect on these channels is largely related to activation of PI3K, whereas the insulin effect appeared to be more dependent on mitogen-activated protein kinase activation.…”

Section: Insulin Leptin and The Control Of Neuronal Ion Channelsmentioning

confidence: 95%

Insulin Signaling in the Central Nervous System

2005

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Insulin and its signaling systems are implicated in both central and peripheral mechanisms governing the ingestion, distribution, metabolism, and storage of nutrients in organisms ranging from worms to humans. Input from the environment regarding the availability and type of nutrients is sensed and integrated with humoral information (provided in part by insulin) regarding the sufficiency of body fat stores. In response to these afferent inputs, neuronal pathways are activated that influence energy flux and nutrient metabolism in the body and ensure reproductive competency. Growing evidence supports the hypothesis that reduced central nervous system insulin signaling from either defective secretion or action contributes to the pathogenesis of common metabolic disorders, including diabetes and obesity, and may therefore help to explain the close association between these two disorders. These considerations implicate insulin action in the brain, an organ previously considered to be insulin independent, as a key determinant of both glucose and energy homeostasis. Diabetes 54: 1264 -1276, 2005 A n important function of the central nervous system (CNS) is to ensure a steady supply of energy substrate to maintain the body economy and prepare for reproduction. To accomplish this task, widely divergent afferent signals must be integrated and transduced into homeostatic adjustments of food intake, energy expenditure, and nutrient metabolism.This perspectives article focuses on recent progress in our understanding of neuronal insulin action and the critical role it plays in energy homeostasis. Based on this information, we hypothesize that the close association between diabetes and obesity in humans arises, at least in part, as a consequence of deficient insulin signaling in both the CNS and peripheral tissues.Studies conducted Ͼ50 years ago first implicated the ventral hypothalamus as a key brain area in energy homeostasis, and an explosion of new information has both confirmed this early impression and illuminated many of the critical mechanisms involved. Among the key findings is evidence that insulin functions not only as a peripheral regulator of nutrient storage and release of circulating substrates but as a key afferent signal to the CNS for the control of energy balance. Indeed, neuronal insulin signaling is known to be important for the control of fat storage in animals as primitive as C. elegans and Drosophilia melanogaster, and the cellular signaling systems mediating these effects bear remarkable homology to those described in mammals. New data have also shown that neuronal insulin signaling is a determinant of lifespan and reproductive function in these organisms, further broadening the importance of this system to diverse areas of physiology and biomedicine.While we note growing evidence implicating insulin action in the control of cognition and neuronal function in cortical and hippocampal areas important to memory formation and information processing, this is not the focus of this article. However, we p...

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Insulin inhibits rat hippocampal neurones via activation of ATP-sensitive K+ and large conductance Ca2+-activated K+ channels

Cited by 57 publications

References 40 publications

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Insulin Activates Native and Recombinant Large Conductance Ca²⁺-Activated Potassium Channels via a Mitogen-Activated Protein Kinase-Dependent Process

Insulin Signaling in the Central Nervous System

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Insulin inhibits rat hippocampal neurones via activation of ATP-sensitive K+ and large conductance Ca2+-activated K+ channels

Cited by 57 publications

References 40 publications

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Insulin Activates Native and Recombinant Large Conductance Ca2+-Activated Potassium Channels via a Mitogen-Activated Protein Kinase-Dependent Process

Insulin Signaling in the Central Nervous System

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Insulin Activates Native and Recombinant Large Conductance Ca²⁺-Activated Potassium Channels via a Mitogen-Activated Protein Kinase-Dependent Process