Multiple Ca<sup>2+</sup> signaling pathways converge on CaM kinase in PC12 cells

MacNicol, Melanie C.; Schulman, Howard

doi:10.1016/0014-5793(92)80627-s

Cited by 78 publications

(22 citation statements)

References 13 publications

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“…Recent findings suggested that ␣7-nAChRs activation led to the neuroprotection against glutamate neurotoxicity via the Ca 2ϩ -dependent phosphatidylinositol 3-kinase pathway, and that nicotine protected neurons by activating phosphatidylinositol 3-kinase, which activated Akt and up-regulated Bcl-2 (Kihara et al, 2001). Furthermore, Ca 2ϩ influx through ␣7-nAChRs could activate Ca 2ϩ /calmodulin-dependent protein kinase-2 in PC12 cells (MacNicol and Schulman, 1992), resulting in nitric-oxide synthase-1 inactivation by its phosphorylation (Nakane et Fig. 6.…”

Section: Discussionmentioning

confidence: 99%

Nicotinic Acetylcholine Receptor-Mediated Neuroprotection by Donepezil Against Glutamate Neurotoxicity in Rat Cortical Neurons

Takada

Yonezawa

Kume

et al. 2003

J Pharmacol Exp Ther

194

126

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Donepezil is a potent and selective acetylcholinesterase (AChE) inhibitor developed for the treatment of Alzheimer's disease. To elucidate whether donepezil shows neuroprotective action in addition to amelioration of cognitive deficits, we examined the effects of donepezil on glutamate-induced neurotoxicity using primary cultures of rat cortical neurons. A 10-min exposure of cultures to glutamate followed by a 1-h incubation with glutamatefree medium caused a marked loss of viability, as determined by Trypan blue exclusion. Glutamate neurotoxicity was prevented by 24-h pretreatment of donepezil in a concentration-dependent manner. Among AChE inhibitors examined, donepezil and certain AChE inhibitors such as tacrine and galanthamine showed potent neuroprotective action, although physostigmine did not affect glutamate neurotoxicity. Neuroprotective action of donepezil was antagonized by mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist, but not by scopolamine, a muscarinic acetylcholine receptor antagonist. Furthermore, both dihydro-␤-erythroidine, an ␣4␤2-neuronal nAChR antagonist, and methyllycaconitine, an ␣7-nAChR antagonist, each also significantly antagonized the effect of donepezil. Next, we examined the effects of donepezil on glutamate-induced apoptosis. Exposure of 100 M glutamate to cortical neurons for 24 h induced apoptotic neuronal death and nuclear fragmentation. Donepezil for 24 h before and 24 h during glutamate exposure prevented nuclear fragmentation and glutamate-induced apoptosis. These results suggest that donepezil not only protects cortical neurons against glutamate neurotoxicity via ␣4␤2-and ␣7-nAChRs but also prevents apoptotic neuronal death.

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Section: Discussionmentioning

confidence: 99%

Nicotinic Acetylcholine Receptor-Mediated Neuroprotection by Donepezil Against Glutamate Neurotoxicity in Rat Cortical Neurons

Takada

Yonezawa

Kume

et al. 2003

J Pharmacol Exp Ther

194

126

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“…Cells washed once with cold Tris-buffered saline plus 1 mM EDTA. Cell lysates were made by resuspending the cell pellet in homogenization buffer (20 mM Tris-HCl, pH 7.5, 0.5 mM EGTA, 1 mM EDTA, 10 mM sodium pyrophosphate, 0.4 mM sodium molybdate, 2 mM dithiothreitol, 0.5% Triton X-100, and protease inhibitors) (50). Cells were kept on ice 10 min with vortexing and then sonicated for 15 s. Total CaM kinase activity in 15 g of sample was assayed by phosphorylation of the CaM kinase-selective substrate syntide-2 (Pro-Leu-AlaArg-Thr-Leu-Ser-Val-Ala-Gly-Leu-Pro-Gly-Lys-Lys, 40 M), in the presence of Ca 2ϩ (0.5 mM) and calmodulin (1.5 g/assay tube) with 5 Ci/ assay tube [␥-…”

Section: Methodsmentioning

confidence: 99%

Calcium/Calmodulin-dependent Protein Kinase IV Is Cleaved by Caspase-3 and Calpain in SH-SY5Y Human Neuroblastoma Cells Undergoing Apoptosis

McGinnis¹,

Whitton²,

Gnegy³

et al. 1998

Journal of Biological Chemistry

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We have previously demonstrated cleavage of ␣-spectrin by caspase-3 and calpain during apoptosis in SH-SY5Y neuroblastoma cells (Nath, R., Raser, K. J., Stafford, D., Hajimohammadreza, I., Posner, A., Allen, H., Talanian, R. V., Yuen, P., Gilbertsen, R. B., and Wang, K. K. (1996) Biochem. J. 319, 683-690). We demonstrate here that calcium/calmodulin-dependent protein kinase IV (CaMK IV) is cleaved during apoptosis by caspase-3 and calpain. We challenged SH-SY5Y cells with the proapoptotic agent thapsigargin. Western blot analysis revealed major CaMK IV breakdown products of 40, 38, and 33 kDa. Digestion of control SH-SY5Y lysate with purified caspase-3 produced a 38-kDa CaMK IV fragment; digestion with purified calpain produced a major fragment of 40 kDa. Pretreatment with carbobenzoxyAsp-CH 2 OC(O)-2,6-dichlorobenzene or Z-Val-Ala-Aspfluoromethylketone was able to block the caspase-3-mediated production of the 38-kDa fragment both in situ and in vitro. Calpain inhibitor II similarly blocked formation of the calpain-mediated 40-kDa fragment both in situ and in vitro. Digestion of recombinant CaMK IV by other caspase family members revealed that only caspase-3 produces a fragmentation pattern consistent to that seen in situ. The major caspase-3 and calpain cleavage sites are respectively identified as PAPD 176 *A and CG 201 *A, both within the CaMK IV catalytic domain. Furthermore, calmodulin-stimulated protein kinase activity decreases within 6 h in thapsigargin-treated SH-SY5Y. The loss of activity precedes cell death.

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“…For these cells, it has been reported previously that ionomycin is able to activate CaM-KII, a kinase that requires CaM to be activated (64). Thus, we have monitored the activation of CaM-KII induced by ionomycin in the presence of different W13 concentrations.…”

Section: Functional Inhibitors Of Cam Prevent the Activation Of The Ementioning

confidence: 99%

Nerve Growth Factor Activation of the Extracellular Signal-Regulated Kinase Pathway Is Modulated by Ca²⁺and Calmodulin

Egea

Espinet

Soler

et al. 2000

Molecular and Cellular Biology

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Nerve growth factor is a member of the neurotrophin family of trophic factors that have been reported to be essential for the survival and development of sympathetic neurons and a subset of sensory neurons. Nerve growth factor exerts its effects mainly by interaction with the specific receptor TrkA, which leads to the activation of several intracellular signaling pathways. Once activated, TrkA also allows for a rapid and moderate increase in intracellular calcium levels, which would contribute to the effects triggered by nerve growth factor in neurons. In this report, we analyzed the relationship of calcium to the activation of the Ras/extracellular signal-regulated kinase pathway in PC12 cells. We observed that calcium and calmodulin are both necessary for the acute activation of extracellular signal-regulated kinases after TrkA stimulation. We analyzed the elements of the pathway that lead to this activation, and we observed that calmodulin antagonists completely block the initial Raf-1 activation without affecting the function of upstream elements, such as Ras, Grb2, Shc, and Trk. We have broadened our study to other stimuli that activate extracellular signal-regulated kinases through tyrosine kinase receptors, and we have observed that calmodulin also modulates the activation of such kinases after epidermal growth factor receptor stimulation in PC12 cells and after TrkB stimulation in cultured chicken embryo motoneurons. Calmodulin seems to regulate the full activation of Raf-1 after Ras activation, since functional Ras is necessary for Raf-1 activation after nerve growth factor stimulation and calmodulin-Sepharose is able to precipitate Raf-1 in a calcium-dependent manner.Neurotrophins (NTs) are neurotrophic factors involved in the development, maintenance, and repair of the nervous system (reviewed in reference 60). This family is composed of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 and neurotrophin 4/5. NGF was the first NT described and has been shown to be essential for the survival and development of sympathetic neurons, some sensory neurons, and a population of cholinergic cells located at the basal forebrain (14,39,94). Each of these NTs exhibits trophic effects on a specific, although partially overlapping, subset of neuronal populations in either the central or the peripheral nervous system both in vivo and in vitro (6, 15). NTs bind to two types of receptors, p75LNTR and the Trk family of tyrosine kinases. All NTs bind to p75 LNTR . However, they show a high degree of specificity for Trk receptors. TrkA is the preferential receptor for NGF, TrkB is that for BDNF and neurotrophin 4/5, and TrkC is that for neurotrophin 3 (5). In the last few years, much attention has been focused on ascertaining the molecular mechanism by which Trk signaling mediates the effects of NTs.The paradigm for studying the intracellular signaling pathways underlying TrkA activation has been the stimulation of this receptor with NGF in the PC12 cell line (38). Once phosphorylated, T...

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Multiple Ca²⁺ signaling pathways converge on CaM kinase in PC12 cells

Cited by 78 publications

References 13 publications

Nicotinic Acetylcholine Receptor-Mediated Neuroprotection by Donepezil Against Glutamate Neurotoxicity in Rat Cortical Neurons

Nicotinic Acetylcholine Receptor-Mediated Neuroprotection by Donepezil Against Glutamate Neurotoxicity in Rat Cortical Neurons

Calcium/Calmodulin-dependent Protein Kinase IV Is Cleaved by Caspase-3 and Calpain in SH-SY5Y Human Neuroblastoma Cells Undergoing Apoptosis

Nerve Growth Factor Activation of the Extracellular Signal-Regulated Kinase Pathway Is Modulated by Ca²⁺and Calmodulin

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Multiple Ca2+ signaling pathways converge on CaM kinase in PC12 cells

Cited by 78 publications

References 13 publications

Nicotinic Acetylcholine Receptor-Mediated Neuroprotection by Donepezil Against Glutamate Neurotoxicity in Rat Cortical Neurons

Nicotinic Acetylcholine Receptor-Mediated Neuroprotection by Donepezil Against Glutamate Neurotoxicity in Rat Cortical Neurons

Calcium/Calmodulin-dependent Protein Kinase IV Is Cleaved by Caspase-3 and Calpain in SH-SY5Y Human Neuroblastoma Cells Undergoing Apoptosis

Nerve Growth Factor Activation of the Extracellular Signal-Regulated Kinase Pathway Is Modulated by Ca2+and Calmodulin

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Multiple Ca²⁺ signaling pathways converge on CaM kinase in PC12 cells

Nerve Growth Factor Activation of the Extracellular Signal-Regulated Kinase Pathway Is Modulated by Ca²⁺and Calmodulin