Abstract
The aim of this study was to elucidate the mechanism of the neurotoxic effect of β-bungarotoxin (β-BuTX, a snake presynaptic neurotoxin isolated from the venom of Bungarus multicinctus) on cultured cerebellar granule neurons. β-BuTX exerted a potent, time-dependent, neurotoxic effect on mature granule neurons. Mature neurons, with an abundance of neurite outgrowths, were obtained after 7-8 days in culture. By means of microspectrofluorimetry and fura-2, we measured the intracellular Ca2+ concentration ([Ca2+]i) and found it to be increased markedly. BAPTA-AM [1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tertrakis(acetoxymethyl ester)], EGTA, MK801 (dizocilpine maleate), and diltiazem prevented not only the elevation of [Ca2+]i, but also the β-BuTX-induced neurotoxic effect. The signaling pathway involved in the elevation of [Ca2+]i in β-BuTX-induced neurotoxicity was studied. The results obtained indicated that β-BuTX initially increased the production of reactive oxygen species and subsequently reduced mitochondrial membrane potential and depleted ATP. All of these events in the signaling pathway were blocked by MK801, diltiazem, EGTA, and BAPTA-AM. These findings suggest that the neurotoxic effect of β-BuTX is mediated, at least in part, by a cascade of events that include the direct or indirect activation of N-methyl-D-aspartate (NMDA) receptors and L-type calcium channels that, in turn, lead to Ca2+ influx, oxidative stress, mitochondrial dysfunction, and ATP depletion. Therefore, we suggest that this polypeptide neurotoxin, as a result of its high potency and irreversible properties, is a useful tool to elucidate the mechanisms of neurodegenerative diseases.
| Original language | English |
|---|---|
| Pages (from-to) | 131-142 |
| Number of pages | 12 |
| Journal | Biochemical Pharmacology |
| Volume | 65 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2003 Jan 1 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Pharmacology
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Neuronal death signaling by β-bungarotoxin through the activation of the N-methyl-D-aspartate (NMDA) receptor and L-type calcium channel. / Tseng, Wen-Pei; Lin-Shiau, Shoei Yn.
In: Biochemical Pharmacology, Vol. 65, No. 1, 01.01.2003, p. 131-142.Research output: Contribution to journal › Article
TY - JOUR
T1 - Neuronal death signaling by β-bungarotoxin through the activation of the N-methyl-D-aspartate (NMDA) receptor and L-type calcium channel
AU - Tseng, Wen-Pei
AU - Lin-Shiau, Shoei Yn
PY - 2003/1/1
Y1 - 2003/1/1
N2 - The aim of this study was to elucidate the mechanism of the neurotoxic effect of β-bungarotoxin (β-BuTX, a snake presynaptic neurotoxin isolated from the venom of Bungarus multicinctus) on cultured cerebellar granule neurons. β-BuTX exerted a potent, time-dependent, neurotoxic effect on mature granule neurons. Mature neurons, with an abundance of neurite outgrowths, were obtained after 7-8 days in culture. By means of microspectrofluorimetry and fura-2, we measured the intracellular Ca2+ concentration ([Ca2+]i) and found it to be increased markedly. BAPTA-AM [1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tertrakis(acetoxymethyl ester)], EGTA, MK801 (dizocilpine maleate), and diltiazem prevented not only the elevation of [Ca2+]i, but also the β-BuTX-induced neurotoxic effect. The signaling pathway involved in the elevation of [Ca2+]i in β-BuTX-induced neurotoxicity was studied. The results obtained indicated that β-BuTX initially increased the production of reactive oxygen species and subsequently reduced mitochondrial membrane potential and depleted ATP. All of these events in the signaling pathway were blocked by MK801, diltiazem, EGTA, and BAPTA-AM. These findings suggest that the neurotoxic effect of β-BuTX is mediated, at least in part, by a cascade of events that include the direct or indirect activation of N-methyl-D-aspartate (NMDA) receptors and L-type calcium channels that, in turn, lead to Ca2+ influx, oxidative stress, mitochondrial dysfunction, and ATP depletion. Therefore, we suggest that this polypeptide neurotoxin, as a result of its high potency and irreversible properties, is a useful tool to elucidate the mechanisms of neurodegenerative diseases.
AB - The aim of this study was to elucidate the mechanism of the neurotoxic effect of β-bungarotoxin (β-BuTX, a snake presynaptic neurotoxin isolated from the venom of Bungarus multicinctus) on cultured cerebellar granule neurons. β-BuTX exerted a potent, time-dependent, neurotoxic effect on mature granule neurons. Mature neurons, with an abundance of neurite outgrowths, were obtained after 7-8 days in culture. By means of microspectrofluorimetry and fura-2, we measured the intracellular Ca2+ concentration ([Ca2+]i) and found it to be increased markedly. BAPTA-AM [1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tertrakis(acetoxymethyl ester)], EGTA, MK801 (dizocilpine maleate), and diltiazem prevented not only the elevation of [Ca2+]i, but also the β-BuTX-induced neurotoxic effect. The signaling pathway involved in the elevation of [Ca2+]i in β-BuTX-induced neurotoxicity was studied. The results obtained indicated that β-BuTX initially increased the production of reactive oxygen species and subsequently reduced mitochondrial membrane potential and depleted ATP. All of these events in the signaling pathway were blocked by MK801, diltiazem, EGTA, and BAPTA-AM. These findings suggest that the neurotoxic effect of β-BuTX is mediated, at least in part, by a cascade of events that include the direct or indirect activation of N-methyl-D-aspartate (NMDA) receptors and L-type calcium channels that, in turn, lead to Ca2+ influx, oxidative stress, mitochondrial dysfunction, and ATP depletion. Therefore, we suggest that this polypeptide neurotoxin, as a result of its high potency and irreversible properties, is a useful tool to elucidate the mechanisms of neurodegenerative diseases.
UR - http://www.scopus.com/inward/record.url?scp=0037212650&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037212650&partnerID=8YFLogxK
U2 - 10.1016/S0006-2952(02)01477-6
DO - 10.1016/S0006-2952(02)01477-6
M3 - Article
C2 - 12473387
AN - SCOPUS:0037212650
VL - 65
SP - 131
EP - 142
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 1
ER -