Transient Opening of the Mitochondrial Permeability Transition Pore Induces Microdomain Calcium Transients in Astrocyte Processes

Agarwal, Amit; Wu, Pei Hsun; Hughes, Ethan G.; Fukaya, Masahiro; Tischfield, Max A.; Langseth, Abraham J.; Wirtz, Denis; Bergles, Dwight E.

doi:10.1016/j.neuron.2016.12.034

Cited by 375 publications

(503 citation statements)

References 54 publications

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“…Astrocyte function is compartmentalized, and little is known about the effect disease conditions have on the homeostasis and function of distinct astrocyte compartments (Agarwal et al, ; Dunn et al, ; Lind et al, ; Oheim, Schmidt, & Hirrlinger, ; Rungta et al, ; Shigetomi et al, ). Using saline and Ang II‐infused GLAST‐CreERT2; R26‐lsl‐GCaMP3 mice, where compartmentalized Ca 2+ activity can be readily assessed, we show increased spontaneous astrocyte Ca 2+ events in MD of hypertensive mice.…”

Section: Discussionmentioning

confidence: 99%

Augmented astrocyte microdomain Ca²⁺ dynamics and parenchymal arteriole tone in angiotensin II‐infused hypertensive mice

Diaz

Kim

Brands

et al. 2018

Glia

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Hypertension is an important contributor to cognitive decline but the underlying mechanisms are unknown. Although much focus has been placed on the effect of hypertension on vascular function, less is understood of its effects on nonvascular cells. Because astrocytes and parenchymal arterioles (PA) form a functional unit (neurovascular unit), we tested the hypothesis that hypertension‐induced changes in PA tone concomitantly increases astrocyte Ca2+. We used cortical brain slices from 8‐week‐old mice to measure myogenic responses from pressurized and perfused PA. Chronic hypertension was induced in mice by 28‐day angiotensin II (Ang II) infusion; PA resting tone and myogenic responses increased significantly. In addition, chronic hypertension significantly increased spontaneous Ca2+ events within astrocyte microdomains (MD). Similarly, a significant increase in astrocyte Ca2+ was observed during PA myogenic responses supporting enhanced vessel‐to‐astrocyte signaling. The transient potential receptor vanilloid 4 (TRPV4) channel, expressed in astrocyte processes in contact with blood vessels, namely endfeet, respond to hemodynamic stimuli such as increased pressure/flow. Supporting a role for TRPV4 channels in aberrant astrocyte Ca2+ dynamics in hypertension, cortical astrocytes from hypertensive mice showed augmented TRPV4 channel expression, currents and Ca2+ responses to the selective channel agonist GSK1016790A. In addition, pharmacological TRPV4 channel blockade or genetic deletion abrogated enhanced hypertension‐induced increases in PA tone. Together, these data suggest chronic hypertension increases PA tone and Ca2+ events within astrocytes MD. We conclude that aberrant Ca2+ events in astrocyte constitute an early event toward the progression of cognitive decline.

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Section: Discussionmentioning

confidence: 99%

Augmented astrocyte microdomain Ca²⁺ dynamics and parenchymal arteriole tone in angiotensin II‐infused hypertensive mice

Diaz

Kim

Brands

et al. 2018

Glia

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“…However, Pr(Mitochondria) was significantly lower than Pr(HW) in small processes and larger than Pr(HW) in thicker processes (the effect of HW: F (19,114) = 16.65, p < .0001; Pr(Mitochondria) vs Pr(HW): F (1,6) = 1.384, p = .28; interaction: F (19,114) = 8.422, p < .0001; n = 7, two‐way RM ANOVA, post hoc Bonferroni's multiple comparison; Supporting Information Figure S2C). This finding suggested that although mitochondria may contribute to astrocytic Ca 2+ activity (Agarwal et al, ), this does not explain the morphology‐dependent Ca 2+ activity observed here.…”

Section: Resultsmentioning

confidence: 53%

“…A recent report suggests that mitochondrial permeability transition pore may transiently open and induces microdomain Ca 2+ transients in astrocytic processes (Agarwal et al, ). If this is the case, Ca 2+ events initiation points should co‐localize with mitochondria.…”

Section: Resultsmentioning

confidence: 99%

Morphological profile determines the frequency of spontaneous calcium events in astrocytic processes

Gordleeva²,

Tang

et al. 2018

Glia

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Astrocytes express a complex repertoire of intracellular Ca2+ transients (events) that represent a major form of signaling within individual cells and in astrocytic syncytium. These events have different spatiotemporal profiles, which are modulated by neuronal activity. Spontaneous Ca2+ events appear more frequently in distal astrocytic processes and independently from each other. However, little is known about the mechanisms underlying such subcellular distribution of the Ca2+ events. Here, we identify the initiation points of the Ca2+ events within the territory of single astrocytes expressing genetically encoded Ca2+ indicator GCaMP2 in culture or in hippocampal slices. We found that most of the Ca2+ events start in an optimal range of thin distal processes. Our mathematical model demonstrated that a high surface‐to‐volume of the thin processes leads to increased amplitude of baseline Ca2+ fluctuations caused by a stochastic opening of Ca2+ channels in the plasma membrane. Suprathreshold fluctuations trigger Ca2+‐induced Ca2+ release from the Ca2+ stores by activating inositol 1,4,5‐trisphosphate (IP3) receptors. In agreement with the model prediction, the spontaneous Ca2+ events frequency depended on the extracellular Ca2+ concentration. Astrocytic depolarization by high extracellular K+ increased the frequency of the Ca2+ events through activation of voltage‐gated Ca2+ channels in cultured astrocytes. Our results suggest that the morphological profile of the astrocytic processes is responsible for tuning of the Ca2+ events frequency. Therefore, structural plasticity of astrocytic processes can be directly translated into changes in astrocytic Ca2+ signaling. This may be important for both physiological and pathological astrocyte remodeling.

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“…Other functional significances of IP 3 R2‐independent Ca 2+ nanodomains around the ER require further clarification. Thus, in addition to extracellular and mitochondrial sources of Ca 2+ that have been clearly indicated as IP 3 R2‐independent Ca 2+ signaling mechanism (Agarwal et al, ; Srinivasan et al, ), IP 3 R2‐independent Ca 2+ release from the ER may contribute to Ca 2+ signaling in IP 3 R2‐KO astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Inositol 1,4,5‐trisphosphate receptor type 2‐independent Ca²⁺ release from the endoplasmic reticulum in astrocytes

Okubo

Kanemaru

Suzuki

et al. 2018

Glia

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Accumulating evidence indicates that astrocytes are actively involved in the physiological and pathophysiological functions of the brain. Intracellular Ca2+ signaling, especially Ca2+ release from the endoplasmic reticulum (ER), is considered to be crucial for the regulation of astrocytic functions. Mice with genetic deletion of inositol 1,4,5‐trisphosphate receptor type 2 (IP3R2) are reportedly devoid of astrocytic Ca2+ signaling, and thus widely used to explore the roles of Ca2+ signaling in astrocytic functions. While functional deficits in IP3R2‐knockout (KO) mice have been found in some reports, no functional deficit was observed in others. Thus, there remains a controversy regarding the functional significance of astrocytic Ca2+ signaling. To address this controversy, we re‐evaluated the assumption that Ca2+ release from the ER is abolished in IP3R2‐KO astrocytes using a highly sensitive imaging technique. We expressed the ER luminal Ca2+ indicator G‐CEPIA1er in cortical and hippocampal astrocytes to directly visualize spontaneous and stimulus‐induced Ca2+ release from the ER. We found attenuated but significant Ca2+ release in response to application of norepinephrine to IP3R2‐KO astrocytes. This IP3R2‐independent Ca2+ release induced only minimal cytosolic Ca2+ transients but induced robust Ca2+ increases in mitochondria that are frequently in close contact with the ER. These results indicate that ER Ca2+ release is retained and is sufficient to increase the Ca2+ concentration in close proximity to the ER in IP3R2‐KO astrocytes.

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Transient Opening of the Mitochondrial Permeability Transition Pore Induces Microdomain Calcium Transients in Astrocyte Processes

Cited by 375 publications

References 54 publications

Augmented astrocyte microdomain Ca²⁺ dynamics and parenchymal arteriole tone in angiotensin II‐infused hypertensive mice

Augmented astrocyte microdomain Ca²⁺ dynamics and parenchymal arteriole tone in angiotensin II‐infused hypertensive mice

Morphological profile determines the frequency of spontaneous calcium events in astrocytic processes

Inositol 1,4,5‐trisphosphate receptor type 2‐independent Ca²⁺ release from the endoplasmic reticulum in astrocytes

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Transient Opening of the Mitochondrial Permeability Transition Pore Induces Microdomain Calcium Transients in Astrocyte Processes

Cited by 375 publications

References 54 publications

Augmented astrocyte microdomain Ca2+ dynamics and parenchymal arteriole tone in angiotensin II‐infused hypertensive mice

Augmented astrocyte microdomain Ca2+ dynamics and parenchymal arteriole tone in angiotensin II‐infused hypertensive mice

Morphological profile determines the frequency of spontaneous calcium events in astrocytic processes

Inositol 1,4,5‐trisphosphate receptor type 2‐independent Ca2+ release from the endoplasmic reticulum in astrocytes

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Augmented astrocyte microdomain Ca²⁺ dynamics and parenchymal arteriole tone in angiotensin II‐infused hypertensive mice

Augmented astrocyte microdomain Ca²⁺ dynamics and parenchymal arteriole tone in angiotensin II‐infused hypertensive mice

Inositol 1,4,5‐trisphosphate receptor type 2‐independent Ca²⁺ release from the endoplasmic reticulum in astrocytes