α7 Nicotinic Receptor Transduces Signals to Phosphatidylinositol 3-Kinase to Block A β-Amyloid-induced Neurotoxicity

Kihara, Takeshi; Shimohama, Shun; Sawada, Hideyuki; Honda, Kazuo; Nakamizo, Tomoki; Shibasaki, Hiroshi; Kume, Toshiaki; Akaike, Akinori

doi:10.1074/jbc.m008035200

Cited by 393 publications

(334 citation statements)

References 33 publications

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“…In the same study, levels of phosphorylated Akt, an effector of PI3K, and Bcl-2, two cell survival proteins, were increased by nicotine. In addition, the ␣7 nAChR was physically associated with PI3K and Fyn in these cells (Kihara et al, 2001). Elevation of A␤ in mouse hippocampus leads to the up-regulation of ␣7 nAChRs, down-regulation of mitogen activated protein kinase (MAPK), and decreased cAMP-regulated element binding protein (CREB) phosphorylation (Dineley et al, 2001), an effect that is opposite to what has been seen with MAPK and CREB with nicotine treatment in PC12 cells (Nakayama et al, 2001).…”

Section: Potential Mechanisms Underlying Nachr-mediated Neuroprotectionmentioning

confidence: 94%

“…Nicotine-induced protection against A␤ in primary cultures of cortical neurons was suppressed by an ␣7 nAChR antagonist, a phosphatidylinositol 3-kinase (PI3K) inhibitor or a Src inhibitor (Kihara et al, 2001). In the same study, levels of phosphorylated Akt, an effector of PI3K, and Bcl-2, two cell survival proteins, were increased by nicotine.…”

Section: Potential Mechanisms Underlying Nachr-mediated Neuroprotectionmentioning

confidence: 99%

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Nicotinic receptors in aging and dementia

2002

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Activation of neuronal nicotinic acetylcholine receptors (nAChRs) has been shown to maintain cognitive function following aging or the development of dementia. Nicotine and nicotinic agonists have been shown to improve cognitive function in aged or impaired subjects. Smoking has also been shown in some epidemiological studies to be protective against the development of neurodegenerative diseases. This is supported by animal studies that have shown nicotine to be neuroprotective both in vivo and in vitro. Treatment with nicotinic agonists may therefore be useful in both slowing the progression of neurodegenerative illnesses, and improving function in patients with the disease. While increased nicotinic function has been shown to be beneficial, loss of cholinergic markers is often seen in patients with dementia, suggesting that decreased cholinergic function could contribute to both the cognitive deficits, and perhaps the neuronal degeneration, associated with dementia. In this article we will review the literature on each of these areas. We will also present hypotheses that might address the mechanisms underlying the ability of nAChR function to protect against neurodegeneration or improve cognition, two potentially distinct actions of nicotine.

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Section: Potential Mechanisms Underlying Nachr-mediated Neuroprotectionmentioning

confidence: 94%

Section: Potential Mechanisms Underlying Nachr-mediated Neuroprotectionmentioning

confidence: 99%

Nicotinic receptors in aging and dementia

2002

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“…First, changes in KYNA often parallel alterations in nAChR function/expression in a number of neurologic disorders (Perry et al, 1990;Hellstrom-Lindahl et al, 1999;Freedman et al, 2000;Court et al, 2001). Second, similarly to NMDA receptors, nAChRs are involved in regulating neuronal plasticity (Albuquerque et al, 1997;Broide and Leslie, 1999;Mansvelder and McGehee, 2000;Ji et al, 2001) and survival in the brain (Zoli et al, 1999;Kihara et al, 2001). Third, the overall effects of ␣7 nAChR antagonists and NMDA receptor antagonists on neuronal plasticity and viability are qualitatively similar and resemble those of KYNA.…”

Section: Kynurenic Acid (Kyna)mentioning

confidence: 99%

Unconventional ligands and modulators of nicotinic receptors

et al. 2002

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ABSTRACT:Evidence gathered from epidemiologic and behavioral studies have indicated that neuronal nicotinic receptors (nAChRs) are intimately involved in the pathogenesis of a number of neurologic disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia. In the mammalian brain, neuronal nAChRs, in addition to mediating fast synaptic transmission, modulate fast synaptic transmission mediated by the major excitatory and inhibitory neurotransmitters glutamate and GABA, respectively. Of major interest, however, is the fact that the activity of the different subtypes of neuronal nAChR is also subject to modulation by substances of endogenous origin such as choline, the tryptophan metabolite kynurenic acid, neurosteroids, and ␤-amyloid peptides and by exogenous substances, including the so-called nicotinic allosteric potentiating ligands, of which galantamine is the prototype, and psychotomimetic drugs such as phencyclidine and ketamine. The present article reviews and discusses the effects of unconventional ligands on nAChR activity and briefly describes the potential benefits of using some of these compounds in the treatment of neuropathologic conditions in which nAChR function/expression is known to be altered.

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“…Src family kinases and phosphatases may also associate with neuronal nAChRs either for regulation of receptor function or for efficient signal transduction (van Hoek et al, 1997). A recent study using immunoprecipitation experiments found that Fyn kinase is physically associated with ␣7-nAChRs solubilized from rat cortical cells in culture, although the methods used would not have necessarily disrupted lipid rafts and the complement of proteins they may bring to the receptors (Kihara et al, 2001).…”

Section: Tethering Components To Neuronal Nicotinic Receptorsmentioning

confidence: 99%

Nicotinic α7 receptors: Synaptic options and downstream signaling in neurons

2002

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Nicotinic receptors are cation-ion selective ligand-gated ion channels that are expressed throughout the nervous system. Most have significant calcium permeabilities, enabling them to regulate calcium-dependent events. One of the most abundant is a species composed of the ␣7 gene product and having a relative calcium permeability equivalent to that of NMDA receptors. The ␣7-containing receptors can be found presynaptically where they modulate transmitter release, and postsynaptically where they generate excitatory responses. They can also be found in perisynaptic locations where they modulate other inputs to the neuron and can activate a variety of downstream signaling pathways. The effects the receptors produce depend critically on the sites at which they are clustered. Instructive preparations for examining ␣7-containing receptors are the rat hippocampus, where they are thought to play a modulatory role, and the chick ciliary ganglion, where they participate in throughput transmission as well as regulatory signaling. Relatively high levels of ␣7-containing receptors are found in the two preparations, and the receptors display a variety of synaptic options and functions in the two cases. Progress is starting to be made in understanding the mechanisms responsible for localizing the receptors at specific sites and in identifying components tethered in the vicinity of the receptors that may facilitate signal transduction and downstream signaling.

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α7 Nicotinic Receptor Transduces Signals to Phosphatidylinositol 3-Kinase to Block A β-Amyloid-induced Neurotoxicity

Cited by 393 publications

References 33 publications

Nicotinic receptors in aging and dementia

Nicotinic receptors in aging and dementia

Unconventional ligands and modulators of nicotinic receptors

Nicotinic α7 receptors: Synaptic options and downstream signaling in neurons

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