Accumulation and extrusion of permeant Ca2+ chelators in attenuation of synaptic transmission at hippocampal CA1 neurons

Ouanounou, Aviv; Zhang, L; Tymianski, Michael; Charlton, Milton P.; Wallace, M. Christopher; Carlen, Peter L.

doi:10.1016/0306-4522(96)00319-3

Cited by 40 publications

(32 citation statements)

References 55 publications

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“…Optical imaging techniques have demonstrated the existence of circadian oscillation of intracellular Ca 2ϩ levels in mammalian clock neurons and plant cells in vitro (Johnson et al, 1995;Colwell, 2000;Ikeda et al, 2003). The highaffinity, rapid-kinetics Ca 2ϩ buffer BAPTA-AM damps and, ultimately, abolishes circadian rhythms of period promoter activity of cultured mammalian clock neurons in vitro without affecting their free-running period (Lundkvist et al, 2005) at concentrations that are high enough to substantially suppress Ca 2ϩ transients and attenuate synaptic communication (Ouanounou et al, 1996). Although these studies suggest the possibility that intracellular Ca 2ϩ signals could be important for regulating freerunning cellular oscillation in vivo, this possibility has not before been tested.…”

Section: Discussionmentioning

confidence: 99%

Intracellular Ca²⁺Regulates Free-Running Circadian Clock OscillationIn Vivo

Harrisingh¹,

Wu²,

Lnenicka³

et al. 2007

J. Neurosci.

118

113

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Although circadian oscillation in dynamics of intracellularbuffering in pacemaker neurons results in dose-dependent slowing of freerunning behavioral rhythms, with average period Ͼ3 h longer than control at the highest dose. The rhythmic nuclear accumulation of a transcription factor known to be essential for cellular circadian oscillation is also slowed. We also determined that Ca 2ϩ buffering interacts synergistically with genetic manipulations that interfere with either calmodulin or calmodulin-dependent protein kinase II function. These results suggest a role for intracellular Ca 2ϩ signaling in regulating intrinsic cellular oscillation in vivo.

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Section: Discussionmentioning

confidence: 99%

Intracellular Ca²⁺Regulates Free-Running Circadian Clock OscillationIn Vivo

Harrisingh¹,

Wu²,

Lnenicka³

et al. 2007

J. Neurosci.

118

113

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“…Also, because these compounds are metabolized (Tsien, 1981 Ouanounou et al, 1996), their kinetics are difficult to predict. Therefore, to determine the cause of the transient neuroprotective action of BAPTA-AM seen presently, we examined the time course of BAPTA retention in the cultures.…”

Section: The Time Course Ofmentioning

confidence: 99%

“…The chelators may act postsynaptically by attenuating neurotoxic NMDA-mediated cytosolic calcium loading (Tymianski et al, 1994a) and /or presynaptically by attenuating excitatory neurotransmitter release (Tymianski et al, 1994b;Ouanounou et al, 1996;Spigelman et al, 1996). Thus, we first examined the role of NMDA receptor activation in OGD toxicity in the present preparation.…”

Section: Ogd Neurotoxicity Is Mediated Partially By Nmda Receptor Actmentioning

confidence: 99%

“…A simpler alternative to manipulating endogenous Ca 2ϩ buffers is to use synthetic, exogenous Ca 2ϩ chelators (Tsien, 1980). The advantages over using Ca 2ϩ binding proteins include a nondisruptive means to introduce the buffers into cells (Tsien, 1981), predictable Ca 2ϩ buffering properties, and the potential for reversing their physiological actions through inactivation and /or cellular extrusion (Ouanounou et al, 1996). The physiological effects of exogenous buffers are well characterized, including their presynaptic effects on attenuating neurotransmitter release (Adler et al, 1991;Niesen et al, 1991;Fredholm and Hu, 1993;Roberts, 1993;Robitaille et al, 1993;Winslow et al, 1994;Ouanounou et al, 1996;Spigelman et al, 1996), postsynaptic effects on neuronal membrane excitability (Marty and Neher, 1985;Lancaster and Nicoll, 1987;Kohr and Mody, 1991;Schwindt et al, 1992;Zhang et al, 1995), and Ca 2ϩ homeostasis (Neher, 1986;Neher and Augustine, 1992;Zhou and Neher, 1993;Tymianski et al, 1994a).…”

Section: Abstract: Calcium; Cell Death; Anoxia; Calcium Buffers; Neumentioning

confidence: 99%

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Mechanisms and Effects of Intracellular Calcium Buffering on Neuronal Survival in Organotypic Hippocampal Cultures Exposed to Anoxia/Aglycemia or to Excitotoxins

Abdel-Hamid¹,

Tymianski

1997

J. Neurosci.

116

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Neuronal calcium loading attributable to hypoxic/ischemic injury is believed to trigger neurotoxicity. We examined in organotypic hippocampal slice cultures whether artificially and reversibly enhancing the Ca 2ϩ buffering capacity of neurons reduces the neurotoxic sequelae of oxygen-glucose deprivation (OGD), whether such manipulation has neurotoxic potential, and whether the mechanism underlying these effects is preor postsynaptic. Neurodegeneration caused over 24 hr by 60 min of OGD was triggered largely by NMDA receptor activation and was attenuated temporarily by pretreating the slices with cell-permeant Ca 2ϩ buffers such as 1,2 bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetra-acetic acid acetoxymethyl ester (BAPTA-AM). This pretreatment produced a transient, reversible increase in intracellular buffer content as demonstrated autoradiographically using slices loaded with 14 C-BAPTA-AM and by confocal imaging of slices loaded with the BAPTA-AM analog calcium green-acetoxymethyl ester (AM). The time courses of 14 C-BAPTA retention and of neuronal survival after OGD were identical, indicating that increased buffer content is necessary for the observed protective effect. Protection by Ca 2ϩ buffering originated presynaptically because BAPTA-AM was ineffective when endogenous transmitter release was bypassed by directly applying NMDA to the cultures, and because pretreatment with the low Ca 2ϩ affinity buffer 2-aminophenol-N,N,O-triacetic acid acetoxymethyl ester, which attenuates excitatory transmitter release, attenuated neurodegeneration. Thus, in cultured hippocampal slices, enhancing neuronal Ca 2ϩ buffering unequivocally attenuates or delays the onset of anoxic neurodegeneration, likely by attenuating the synaptic release of endogenous excitatory neurotransmitters (excitotoxicity).

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“…To maximize the effect of BAPTA-AM at the time of ␣-LTX action, (1) we added an anion pump inhibitor, probenecid (1 mM), to minimize the loss of BAPTA from the cytosol (Ouanounou et al, 1996); (2) we gave a second treatment of BAPTA-AM 15 min after the first (final concentration 200 M) to get a longer-lasting effect of the chelator; and (3) we added ␣-LTX at 10 times the normal concentration to hasten the action of the toxin (time to onset, Ͻ2 min) 15 min after the second BAPTA-AM addition. Following these criteria ensured that the effects of ␣-LTX were observed when Ca 2ϩ buffering was at its strongest.…”

Section: Relationship Between Ca 2؉ and ␣-Ltx-induced Transmitter Relmentioning

confidence: 99%

α-Latrotoxin Releases Calcium in Frog Motor Nerve Terminals

2000

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α-Latrotoxin (α-LTX) is a neurotoxin that accelerates spontaneous exocytosis independently of extracellular Ca2+. Although α-LTX increases spontaneous transmitter release at synapses, the mechanism is unknown. We tested the hypothesis that α-LTX causes transmitter release by mobilizing intracellular Ca2+in frog motor nerve terminals. Transmitter release was measured electrophysiologically and with the vesicle marker FM1-43; presynaptic ion concentration dynamics were measured with fluorescent ion-imaging techniques. We report that α-LTX increases transmitter release after release of a physiologically relevant concentration of intracellular Ca2+. Neither the blockade of Ca2+release nor the depletion of Ca2+from endoplasmic reticulum affected Ca2+signals produced by α-LTX. The Ca2+source is likely to be mitochondria, because the effects on Ca2+mobilization of CCCP (which depletes mitochondrial Ca2+) and of α-LTX are mutually occlusive. The release of mitochondrial Ca2+is partially attributable to an increase in intracellular Na+, suggesting that the mitochondrial Na+/Ca2+exchanger is activated. Effects of α-LTX were not blocked when Ca2+increases were reduced greatly in saline lacking both Na+and Ca2+and by application of intracellular Ca2+chelators. Therefore, although increases in intracellular Ca2+may facilitate the effects of α-LTX on transmitter release, these increases do not appear to be necessary. The results show that investigations of Ca2+-independent α-LTX mechanisms or uses of α-LTX to probe exocytosis mechanisms would be complicated by the release of intracellular Ca2+, which itself can trigger exocytosis.

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Accumulation and extrusion of permeant Ca2+ chelators in attenuation of synaptic transmission at hippocampal CA1 neurons

Cited by 40 publications

References 55 publications

Intracellular Ca²⁺Regulates Free-Running Circadian Clock OscillationIn Vivo

Intracellular Ca²⁺Regulates Free-Running Circadian Clock OscillationIn Vivo

Mechanisms and Effects of Intracellular Calcium Buffering on Neuronal Survival in Organotypic Hippocampal Cultures Exposed to Anoxia/Aglycemia or to Excitotoxins

α-Latrotoxin Releases Calcium in Frog Motor Nerve Terminals

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Accumulation and extrusion of permeant Ca2+ chelators in attenuation of synaptic transmission at hippocampal CA1 neurons

Cited by 40 publications

References 55 publications

Intracellular Ca2+Regulates Free-Running Circadian Clock OscillationIn Vivo

Intracellular Ca2+Regulates Free-Running Circadian Clock OscillationIn Vivo

Mechanisms and Effects of Intracellular Calcium Buffering on Neuronal Survival in Organotypic Hippocampal Cultures Exposed to Anoxia/Aglycemia or to Excitotoxins

α-Latrotoxin Releases Calcium in Frog Motor Nerve Terminals

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Intracellular Ca²⁺Regulates Free-Running Circadian Clock OscillationIn Vivo

Intracellular Ca²⁺Regulates Free-Running Circadian Clock OscillationIn Vivo