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The Journal of Neuroscience, September 30, 2009, 29(39):12101-12114; doi:10.1523/JNEUROSCI.3384-09.2009

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Cellular/Molecular
Mitochondrial Ca²⁺ Cycling Facilitates Activation of the Transcription Factor NFAT in Sensory Neurons

Man-Su Kim and Yuriy M. Usachev

Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242

Correspondence should be addressed to Yuriy M. Usachev, Department of Pharmacology, University of Iowa Carver College of Medicine, 2-250 BSB, 51 Newton Road, Iowa City, IA 52242. Email: yuriy-usachev{at}uiowa.edu

Ca²⁺-dependent gene regulation controls many aspects of neuronal plasticity. Significant progress has been made toward understanding the roles of voltage- and ligand-gated Ca²⁺ channels in triggering specific transcriptional responses. In contrast, the functional importance of Ca²⁺ buffers and Ca²⁺ transporters in neuronal gene regulation is less clear despite their critical contribution to the spatiotemporal control of Ca²⁺ signals. Here we examined the role of mitochondrial Ca²⁺ uptake and release in regulating the Ca²⁺-dependent transcription factor NFAT (nuclear factor of activated T-cells), which has been implicated in synaptic plasticity, axonal growth, and neuronal survival. Intense stimulation of sensory neurons by action potentials or TRPV1 agonists induced rapid activation and nuclear import of NFAT. Nuclear translocation of NFAT was associated with a characteristic prolonged [Ca²⁺]_i elevation (plateau) that resulted from Ca²⁺ uptake by, and its subsequent release from, mitochondria. Measurements using a mitochondrial Ca²⁺ indicator, mtPericam, showed that this process recruited mitochondria throughout the cell body, including the perinuclear region. [Ca²⁺]_i levels attained during the plateau phase were similar to or higher than those required for NFAT activation (200–300 nM). The elimination of the [Ca²⁺]_i plateau by blocking either mitochondrial Ca²⁺ uptake via the uniporter or Ca²⁺ release via the mitochondrial Na⁺/Ca²⁺ exchanger strongly reduced nuclear import of NFAT. Furthermore, preventing Ca²⁺ mobilization via the mitochondrial Na⁺/Ca²⁺ exchanger diminished NFAT-mediated transcription. Collectively, these data implicate activity-induced Ca²⁺ uptake and prolonged release from mitochondria as a novel regulatory mechanism in neuronal excitation–transcription coupling.

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Received July 14, 2009; accepted Aug. 14, 2009.

Correspondence should be addressed to Yuriy M. Usachev, Department of Pharmacology, University of Iowa Carver College of Medicine, 2-250 BSB, 51 Newton Road, Iowa City, IA 52242. Email: yuriy-usachev{at}uiowa.edu

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