Mitochondrial Ca2+ cycling facilitates activation of the transcription factor NFAT in sensory neurons.
Ca(2+)-dependent gene regulation controls many aspects of neuronal plasticity. Significant progress has been made toward understanding the roles of voltage- and ligand-gated Ca(2+) channels in triggering specific transcriptional responses. In contrast, the functional importance of Ca(2+) buffers and Ca(2+) transporters in neuronal gene regulation is less clear despite their critical contribution to the spatiotemporal control of Ca(2+) signals. Here we examined the role of mitochondrial Ca(2+) uptake and release in regulating the Ca(2+)-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 [Ca(2+)](i) elevation (plateau) that resulted from Ca(2+) uptake by, and its subsequent release from, mitochondria. Measurements using a mitochondrial Ca(2+) indicator, mtPericam, showed that this process recruited mitochondria throughout the cell body, including the perinuclear region. [Ca(2+)](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 [Ca(2+)](i) plateau by blocking either mitochondrial Ca(2+) uptake via the uniporter or Ca(2+) release via the mitochondrial Na(+)/Ca(2+) exchanger strongly reduced nuclear import of NFAT. Furthermore, preventing Ca(2+) mobilization via the mitochondrial Na(+)/Ca(2+) exchanger diminished NFAT-mediated transcription. Collectively, these data implicate activity-induced Ca(2+) uptake and prolonged release from mitochondria as a novel regulatory mechanism in neuronal excitation-transcription coupling.
Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
Man-Su
MS
Kim
Yuriy M
YM
Usachev
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D008928:Mitochondria / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D050778:NFATC Transcription Factors; D050916:TRPV Cation Channels; D014157:Transcription Factors; C493922:Trpv1 protein, rat; D002118:Calcium