Potassium channel dysfunction in fibroblasts identifies patients with Alzheimer disease.

Etcheberrigaray, René; Ito, Etsuro; Oka, Kotaro; Tofel-Grehl, Beth; Gibson, Gary E.; Alkon, Daniel L.

doi:10.1073/pnas.90.17.8209

Cited by 120 publications

(59 citation statements)

References 38 publications

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“…1D). As previously determined (5), to reach a standard density (50 cells per mm2 after seeding at 5 cells per mm2) for analysis, fibroblasts from AD, AC, ND, and YC donors required virtually the same time in culture [AD, 3.5 ± 0.1 days (mean ± SEM), n = 10; AC, 3.4 ± 0.1 days, n = 8; YC, 3.6 ± 0.2 days, n = 6; all n values refer to the number of cell lines unless otherwise specified]. Furthermore, Ca2+ signal characteristics were not at all correlated with the number of passages in tissue culture (Fig.…”

Section: Methodsmentioning

confidence: 63%

“…Ca2+ signals elicited by perfusion with elevated external K+ have been shown not to differ between AD and AC cells (5). Ca2+ channel blockers completely eliminated all Ca2+ signals elicited (presumably by depolarization-induced Ca2+ influx) with elevated external K+ (n = 11) (5).…”

Section: Resultsmentioning

confidence: 99%

“…Human skin fibroblasts (Table 1) were purchased from the Coriell Cell Repositories (Camden, NJ). Cells were seeded and maintained as described (5). The number of passages was not significantly different between groups [AD, 10.9 ± 1.3 (mean ± SEM), n = 10; AC, 11.5 + 0.8, n = 8; YC, 8.4 ± 1.0, n = 6] and always <20 (see also Fig.…”

Section: Methodsmentioning

confidence: 99%

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Internal Ca2+ mobilization is altered in fibroblasts from patients with Alzheimer disease.

Ito

Oka

Etcheberrigaray

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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The recent demonstration of K+ channel dysfunction in fibroblasts from Alzheimer disease (AD) patients and past observations of Ca2+-mediated K+ channel modulation during memory storage suggested that AD, which is characterized by memory loss and other cognitive deficits, might also involve dysfunction of intracellular Ca2+ mobilization. Bombesin-induced Ca2+ release, which is inositol trisphosphate-mediated, is shown here to be greatly enhanced in AD fibroblasts compared with fibroblasts from control groups. Bradykinin, another activator of phospholipase C, elicits similar enhancement of Ca2+ signaling in AD fibroblasts. By contrast, thapsigargin, an agent that releases Ca2+ by direct action on the endoplasmic reticulum, produced no differences in Ca2+ increase between AD and control fibroblasts. Depolarization-induced Ca2+ influx data previously demonstrated the absence of between-group differences of Ca2+ pumping and/or buffering. There was no correlation between the number of passages in tissue culture and the observed Ca2+ responses. Furthermore, cells of all groups were seeded and analyzed at the same densities. Radioligand binding experiments indicated that the number and affinity of bombesin receptors cannot explain the observed differences. These and previous observations suggest that the differences in bombesin and bradykinin responses in fibroblasts and perhaps other cell types are likely to be due to alteration of inositol trisphosphatemediated release of intracellular Ca2+.A number of cellular changes have been observed in fibroblasts from patients with Alzheimer disease (AD). These include abnormality of glucose and energy-related metabolism (1), defective release of a cholinergic factor (2), abnormal f8-amyloid expression and processing (3), changes in Ca2+ metabolism (30-34), and altered p-adrenergic-induced cAMP formation (4). The recent demonstration of K+ channel dysfunction in AD fibroblasts (5, 6) and past observations of Ca2+-mediated K+ channel modulation during memory storage (7) suggested that AD, which is characterized by memory loss and other cognitive deficits (8, 9), might also involve dysfunction of intracellular Ca2+ mobilization. Bombesin (10-12), an agent that activates phospholipase C (PLC) to generate inositol 1,4,5-trisphosphate (1P3) (13)(14)(15) different for AD and control fibroblasts. f-Amyloid protein (23-25) itself, while causing the previously observed inactivation of K+ channels in AD fibroblasts, had no effect on the bombesin-elicited Ca2+ signals. These and other findings, together with measurements of bombesin receptor number, suggest that PLC/G-protein coupling and/or IP3 receptors are responsible for differences in Ca2+ responses between AD and non-AD fibroblasts. METHODSCell Lines. Human skin fibroblasts (Table 1) were purchased from the Coriell Cell Repositories (Camden, NJ). Cells were seeded and maintained as described (5). The number of passages was not significantly different between groups [AD, 10.9 ± 1.3 (mean ± SEM), n = 10; AC, 11.5 + 0.8, n = 8;...

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Section: Methodsmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Internal Ca2+ mobilization is altered in fibroblasts from patients with Alzheimer disease.

Ito

Oka

Etcheberrigaray

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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301

224

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“…Even though several groups have investigated Aẽ ffects on membrane ion channels (Etcheberrigaray et al, 1993(Etcheberrigaray et al, , 1994Davidson et al, 1994;Good et al, 1996;Ueda et al, 1997), the role of ion channels in A/3-induced cell death remains controversial and poorly understood. In neurons, K + channels set the resting potential, keep fast action potentials short, terminate periods of intense activity, time interspike intervals during repetitive firing, and lower the effectiveness of excitatory inputs (Hille, 1992).…”

Section: ~]mentioning

confidence: 99%

Role of Potassium Channels in Amyloid‐Induced Cell Death

Colom

Díaz

Beers

et al. 1998

Journal of Neurochemistry

145

121

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Basal forebrain cholinergic neurons are severely depleted early in Alzheimer's disease and appear particularly susceptible to amyloid /3-peptide (A/3) toxicity in vivo. To model this effect in vitro, a cholinergic septal cell line (SN56) was exposed to Af3. SN56 cells exhibited a tetraethylammonium (TEA)-sensitive outward Kcurrent with delayed rectifier characteristics. Increases of 64% (±19; p < 0.02) and 44% (±12; p < 0.02) in Kc urrent density were noted 6-12 and 12-18 h following the addition of A~3to SN56 cell cultures, respectively. Morphological observation and staining for cell viability showed that 25 ± 4 and 39 ± 4% of SN56 cells were dead after 48-and 96-h exposures to A~,respectively. Perfusion of SN56 cells with 10-20 mMTEA blocked 71 ± 6 to 92 ± 2% of the outward currents, widened action potentials, elevated [Ca 2~],,and inhibited 89 ± 14 and 68 ±

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“…Moreover, several reports suggest the properties of APP derivatives are closely related to Ca2+ and K+ ion channels Lahiri et al 1992;Nitsch et al 1992;Arispe et al 1993;Etcheberrigaray et al 1994;Weiss et al 1994). This could be related to the dysfunction of both channels in fibroblasts and lymphocytes which has been found in the patients of Alzheimer's disease Eckert et al 1993;Etcheberrigaray et al 1993;McCoy et al 1993;. Although extensive studies on the APP metabolism and its possible effects on cell metabolism had been done, there are still a little information about whether APP expressed on neurons could provide above functions in the intact nervous system and even in vitro.…”

Section: Pkc Content and Its Activitymentioning

confidence: 99%

The Decrement of Muscarinic Receptor-Mediated Calcium Influx by Overexpression of APP in a Mouse Cholinergic Cell Line.

Kunishita¹,

Ikeda²,

Araki³

et al. 1994

Tohoku J. Exp. Med.

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The effects of f3-amyloid precursor protein (APP) overexpressing on cell metabolisms of cholinergic neuronal hybridoma cell line (SN49) were examined. The cells stably overexpressing APP contained higher amount of GTP binding protein Go and cytosolic inactive protein kinase Ce, and showed less Ca2+ influx through muscarinic acetylcholine receptor ml compared to original and mock cells which had been transfected with a vector alone. The contents of sn-1, 2-diacylglycerol and cycilc AMP were also reduced in the APP transfectants, although the similar changes were observed in the mock cells. These findings strongly suggest that the overexpression of APP affect the transient receptor-mediated ion channel and calcium-related cell metabolisms in neuronal cells.APP overexpression; cholinergic cell line; muscarinic receptor; protein kinase C; GTP binding protein Deposition of f3-amyloid protein (fAP), which is composed of 39-42 of amino acids, in the brain was one of the major pathological hall-marks in Alzheimer's disease and aged Down's syndrome. fAP is generated by the cleavage of its precursor protein (APP 695, 751 and 770), 100-140 KDa integral mambrane proteins produced by three of alternative spliced mRNA from a gene on human chromosome 21. Proteolytic cleavage between residues 595 and 596 of APP695 forms amyloidogenic C-terminal fragments containing /3AP , while it between residue 612 and 163 produces non-amyloidogenic C-terminal fragments containing P3 (Haass et al. 1993). At least three of APP fragments are normally released to extra-cellular space by either so called c -or f3-secretary pathway. That is, secreted APPS (sAPP) and P3 are processed by a-pathway

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Potassium channel dysfunction in fibroblasts identifies patients with Alzheimer disease.

Cited by 120 publications

References 38 publications

Internal Ca2+ mobilization is altered in fibroblasts from patients with Alzheimer disease.

Internal Ca2+ mobilization is altered in fibroblasts from patients with Alzheimer disease.

Role of Potassium Channels in Amyloid‐Induced Cell Death

The Decrement of Muscarinic Receptor-Mediated Calcium Influx by Overexpression of APP in a Mouse Cholinergic Cell Line.

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