Presynaptic Mitochondrial Calcium Sequestration Influences Transmission at Mammalian Central Synapses

Billups, Brian; Forsythe, Ian D.

doi:10.1523/jneurosci.22-14-05840.2002

Cited by 366 publications

(342 citation statements)

References 75 publications

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“…Mitochondria are abundant in the synaptic terminals of neurons that are capable of firing at high frequencies (Rowland et al 2000;Tolbert and Morest 1982) and are known to be involved in presynaptic responses to high-frequency stimulation including posttetanic potentiation (Friel and Tsien 1994;Jonas et al 1999;Tang and Zucker 1997) and in recovery of neurotransmission after synaptic depression (Billups and Forsythe 2002;. Injection of BCL-xL into the presynaptic terminal increases the rate of recovery of transmitter release after a period of rapid firing , suggesting that it enhances the performance of mitochondria in recovery.…”

Section: Resultsmentioning

confidence: 99%

Bcl-xL Inhibitor ABT-737 Reveals a Dual Role for Bcl-xL in Synaptic Transmission

Hickman

Hardwick

Kaczmarek

et al. 2008

Journal of Neurophysiology

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A role for BCL-xL in regulating neuronal activity is suggested by its dramatic effects on synaptic function and mitochondrial channel activity. When recombinant BCL-xL is injected into the giant presynaptic terminal of squid stellate ganglion or applied directly to mitochondrial outer membranes within the living terminal, it potentiates synaptic transmission acutely, and it produces mitochondrial channel activity. The squid, however, is a genetically intractable model, making it difficult to apply genetic tools in squid to explore the role of endogenous BCL-xL in synaptic function. Therefore the small molecule inhibitor ABT-737, a mimetic of the BH3-only protein BAD, binding to the BH3-binding domain pocket, was tested in squid, revealing a dual role for BCL-xL. ABT-737 slowed recovery of synaptic responses after repetitive synaptic activity, indicating that endogenous BCL-xL is necessary for timely recovery of rapidly firing synapses. Unexpectedly, however, ABT-737 also protected neurons from hypoxia-induced synaptic rundown and from increased permeability of the mitochondrial outer membrane during hypoxia. This implies that endogenous BCL-xL or a modified form of BCL-xL, such as the N-truncated, proteolytic, pro-apoptotic cleavage product, ΔN BCL-xL, contributes to injurious responses of the hypoxic synapse. To determine if ABT-737 is also an inhibitor of ΔN BCL-xL, recombinant ΔN BCL-xL protein was injected into the synapse. ABT-737 potently inhibited synaptic rundown induced by recombinant ΔN BCL-xL. These observations support the possibility that endogenous proteolysis or a functionally equivalent modification of BCLxL is responsible for the deleterious effects of hypoxia on synaptic activity.

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Section: Resultsmentioning

confidence: 99%

Bcl-xL Inhibitor ABT-737 Reveals a Dual Role for Bcl-xL in Synaptic Transmission

Hickman

Hardwick

Kaczmarek

et al. 2008

Journal of Neurophysiology

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“…However, the discrepancy in the size of the initial [Ca 2+ ] M peak may also be due to the high affinity of the dye. In fact, the lower affinity dye rhod-FF (Kd = 19 M) has been used in some cases to avoid saturation with Ca 2+ or to minimize the signal coming from mistargeted cytosolic dye [17,18]. In these papers, although the data were not calibrated in [Ca 2+ ] values, it was actually shown that rhod-2 saturated with Ca 2+ in mitochondria during cell stimulation, while rhod-FF had a better response.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of mitochondrial [Ca2+] measured with the low-Ca2+-affinity dye rhod-5N

et al. 2012

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a b s t r a c tAvailable methods to measure mitochondrial [Ca 2+ ] ([Ca 2+ ] M ) include both targeted proteins and fluorescent dyes. Targeted proteins usually report much higher [Ca 2+ ] M values than fluorescent dyes, up to two orders of magnitude. However, we show here that the low-Ca 2+ -affinity dye rhod-5N provides [Ca 2+ ] M values similar to those reported by targeted aequorin, suggesting that the discrepancies are mainly due to the higher Ca 2+ -affinity of the fluorescent dyes used. We find rhod-5N has an apparent in situ intramitochondrial Kd around 0.5 mM. Addition of Ca 2+ buffers containing between 4.5 and 10 M [Ca 2+ ] to permeabilized cells loaded with rhod-5N induced increases in calibrated [Ca 2+ ] M up to the 100 M-1 mM range, which were dependent on mitochondrial membrane potential. Ca 2+ release from mitochondria was largely dependent on [Na + ]. We have then used rhod-5N loaded cells to investigate the [Ca 2+ ] M response to agonist stimulation at the single-cell and subcellular level.The [Ca 2+ ] M peaks induced by histamine varied by nearly 10-fold among different cells, with a mean about 25 M. In the presence of the Ca 2+ uniporter stimulator kaempferol, the [Ca 2+ ] M peaks induced by histamine were also highly variable, and the mean [Ca 2+ ] M peak was 3-fold higher. Simultaneous measurement of cytosolic and mitochondrial [Ca 2+ ] peaks showed little correlation among the heights of the peaks in both compartments. Studying the [Ca 2+ ] M peaks at the subcellular level, we found significant heterogeneities among regions in the same cell. In particular, the [Ca 2+ ] M increase in mitochondrial regions close to the nucleus was more than double that of mitochondrial regions far from the nucleus.

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“…Similarly, mitochondria have experienced a comeback as transient Ca 2ϩ stores also under physiological conditions (Pozzan and Rizzuto, 2000), contrasting the earlier view that these organelles contribute to Ca 2ϩ homeostasis primarily under pathologic conditions (excitotoxicity, apoptosis). Mitochondria participate in Ca 2ϩ removal during muscle relaxation in slow-twitch (Sembrowich et al, 1985;Gillis, 1997) and fast-twitch muscles (Rudolf et al, 2004); in neurons they also contribute to the presynaptic regulation of Ca 2ϩ transients (Billups and Forsythe, 2002). Besides the anticipated slowing of muscle relaxation in PVϪ/Ϫ mice, a twofold increase in mitochondrial volume density is observed that is viewed as a specific homeostatic compensation mechanism (Chen et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…These organelles have a high capacity to take up Ca 2ϩ , but affinity and the speed of uptake were previously considered too low to sequester Ca 2ϩ under physiological conditions in neurons (Carafoli, 2002). A role for mitochondria in the presynaptic regulation of Ca 2ϩ transients was demonstrated in the calyx of Held (Billups and Forsythe, 2002). With a half-rise time of approximately 40 ms, mitochondrial Ca 2ϩ ([Ca 2ϩ ] m ) rose with a short delay when compared with [Ca 2ϩ ] i rises.…”

mentioning

confidence: 99%

Deficiency in parvalbumin, but not in calbindin D-28k upregulates mitochondrial volume and decreases smooth endoplasmic reticulum surface selectively in a peripheral, subplasmalemmal region in the soma of Purkinje cells

et al. 2006

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Abstract-The Ca 2؉ -binding proteins parvalbumin (PV) and calbindin D-28k (CB) are key players in the intracellular Ca 2؉ -buffering in specific cells including neurons and have profound effectson spatiotemporal aspects of Ca 2؉ transients. The previously observed increase in mitochondrial volume density in fast-twitch muscle of PV؊/؊ mice is viewed as a specific compensation mechanism to maintain Ca 2؉ homeostasis. Since cerebellar Purkinje cells (PC) are characterized by high expression levels of the Ca 2؉ buffers PV and CB, the question was raised, whether homeostatic mechanisms are induced in PC lacking these buffers. Mitochondrial volume density, i.e. relative mitochondrial mass was increased by 40% in the soma of PV؊/؊ PC. Upregulation of mitochondrial volume density was not homogenous throughout the soma, but was selectively restricted to a peripheral region of 1.5 m width underneath the plasma membrane. Accompanied was a decreased surface of subplasmalemmal smooth endoplasmic reticulum (sPL-sER) in a shell of 0.5 m thickness underneath the plasma membrane. These alterations were specific for the absence of the "slow-onset" buffer PV, since in CB؊/؊ mice neither changes in peripheral mitochondria nor in sPL-sER were observed. This implicates that the morphological alterations are aimed to specifically substitute the function of the slow buffer PV. We propose a novel concept that homeostatic mechanisms of components involved in Ca 2؉ homeostasis do not always occur at the level of similar or closely related molecules. Rather the cell attempts to restore spatiotemporal aspects of Ca 2؉ signals prevailing in the undisturbed (wildtype) situation by subtly fine tuning existing components involved in the regulation of Ca 2؉ fluxes.Key words: calcium-binding, buffers, EF-hand, homeostasis, morphology.Ca 2ϩ ions are such ubiquitous second messengers that meaningful information must be contained in the subtle spatiotemporal aspects of Ca 2ϩ transients. A complex machinery of Ca 2ϩ entry and release systems, mobile and immobile Ca 2ϩ buffers, transient Ca 2ϩ -storage devices and Ca 2ϩ -extrusion systems governs the shape and spreading of intracellular Ca 2ϩ transients (Berridge et al., 2003). Affinities, kinetics of binding and release of Ca 2ϩ ions, the relative mobility and the geometrical distribution of all components, that is, the interplay between these systems finally shapes the spatiotemporal aspects of a Ca 2ϩ signal. Cerebellar Purkinje cells (PC) are characterized by extensive Ca 2ϩ signaling in somata, dendrites and spines elicited by either climbing fiber or parallel fiber stimulation. Following depolarization-evoked rises in the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) in the PC somata, endoplasmic reticulum (ER) and plasma membrane Ca 2ϩ pumps and the Na ϩ -Ca 2ϩ exchanger contribute to PC [Ca 2ϩ ] i clearance (Fierro et al., 1998). Since these systems only accounted for approximately 60% of total Ca 2ϩ clearing, mitochondria were additionally postulated to play a role. These organelles have...

show abstract

Presynaptic Mitochondrial Calcium Sequestration Influences Transmission at Mammalian Central Synapses

Cited by 366 publications

References 75 publications

Bcl-xL Inhibitor ABT-737 Reveals a Dual Role for Bcl-xL in Synaptic Transmission

Bcl-xL Inhibitor ABT-737 Reveals a Dual Role for Bcl-xL in Synaptic Transmission

Dynamics of mitochondrial [Ca2+] measured with the low-Ca2+-affinity dye rhod-5N

Deficiency in parvalbumin, but not in calbindin D-28k upregulates mitochondrial volume and decreases smooth endoplasmic reticulum surface selectively in a peripheral, subplasmalemmal region in the soma of Purkinje cells

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