Transcriptional coupling of synaptic transmission and energy metabolism: Role of nuclear respiratory factor 1 in co-regulating neuronal nitric oxide synthase and cytochrome c oxidase genes in neurons

Dhar, S.; Liang, Huan; Wong‐Riley, Margaret T.T.

doi:10.1016/j.bbamcr.2009.07.001

Cited by 28 publications

(29 citation statements)

References 51 publications

(101 reference statements)

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“…Moreover, most successful studies in NRF-1 silencing employed mouse cell lines (37)(38)(39). Using human cell lines, Asangani et al (33) reported on the silencing of NRF-1, however, the latter brought about only 30% reduction in the studied NRF-1 target gene, calpain small subunit 1 (CAPNS1).…”

Section: Identification and Functional Characterization Of Nrf-1 Bindmentioning

confidence: 99%

The Obligatory Intestinal Folate Transporter PCFT (SLC46A1) Is Regulated by Nuclear Respiratory Factor 1

Gonen

Assaraf

2010

Journal of Biological Chemistry

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Folates are essential vitamins that play a key role as onecarbon donors in a spectrum of biosynthetic pathways including RNA and DNA synthesis. The proton-coupled folate transporter (PCFT/SLC46A1) mediates obligatory intestinal folate absorption. Loss-of-function mutations in PCFT result in hereditary folate malabsorption, an autosomal recessive disorder characterized by very low folate levels in the blood and cerebrospinal fluid. Hereditary folate malabsorption manifests within the first months after birth with anemia, immune deficiency, and neurological deficits. Here we studied the role of inducible trans-activators of PCFT gene expression. Bioinformatics identified three putative nuclear respiratory factor 1 (NRF-1) binding sites in the minimal promoter. The following evidence establish that PCFT is an NRF-1-responsive gene; electrophoretic mobility shift assay showed NRF-1 binding to native but not mutant NRF-1 sites, whereas antibody-mediated supershift analysis and chromatin immunoprecipitation revealed NRF-1 binding to its consensus sites within the PCFT promoter. Moreover, mutational inactivation of individual or all NRF-1 binding sites resulted in 40 -60% decrease in luciferase reporter activity. Consistently, overexpression of NRF-1 or a constitutively active NRF-1 VP-16 construct resulted in increased reporter activity and PCFT mRNA levels. Conversely, introduction of a dominant-negative NRF-1 construct markedly repressed reporter activity and PCFT mRNA levels; likewise, introduction of NRF-1 siRNA duplexes to cells resulted in decreased PCFT transcript levels. Moreover, NRF-1 silencing down-regulated genes encoding for key folate transporters and enzymes in folate metabolism. These novel findings identify NRF-1 as a major inducible transcriptional regulator of PCFT gene expression. The implications of this linkage between folate transport and metabolism with mitochondria biogenesis and respiration are discussed.

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Section: Identification and Functional Characterization Of Nrf-1 Bindmentioning

confidence: 99%

The Obligatory Intestinal Folate Transporter PCFT (SLC46A1) Is Regulated by Nuclear Respiratory Factor 1

Gonen

Assaraf

2010

Journal of Biological Chemistry

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“…Transfected neurons were stimulated with KCl at a final concentration of 20 mM in the culture media for 5 h as previously described [22]. After 5 h of treatment, cell lysates were harvested and measured for luciferase activity as described previously [22]. Data from six independent transfections were averaged for each promoter construct.…”

Section: Methodsmentioning

confidence: 99%

“…Transfection efficiency for N2a cells was around 75%; however, puromycin selection effectively yielded 100% transfected cells. N2a cells transfected with shRNA against NRF-2 were further stimulated with KCl at a final concentration of 20 mM in the culture media for 5 h as previously described [22]. After 5 h of treatment, cells were harvested for RNA isolation.…”

Section: Methodsmentioning

confidence: 99%

“…Green fluorescence was used to monitor transfection efficiency. Transfected neurons were impulse blocked for 3 days with TTX at a final concentration of 0.4 μM, starting the day after plating as previously described [22]. Four days after transfection, cells were harvested for RNA isolation.…”

Section: Methodsmentioning

confidence: 99%

“…Real-time quantitative PCR was carried out in a Cepheid Smart Cycler Detection system (Cepheid, Sunnyvale, CA, USA) and/or the iCycler System (BioRad) using the IQ Sybr Green SuperMix (170-8880, BioRad) following the manufacturer’s protocols and as described previously [22]. The primer sequences used are shown in Table 5.…”

Section: Methodsmentioning

confidence: 99%

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Nuclear respiratory factor 2 regulates the transcription of AMPA receptor subunit GluA2 (Gria2)

Priya

Johar

Nair

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Neuronal activity is highly dependent on energy metabolism. Nuclear respiratory factor 2 (NRF-2) tightly couples neuronal activity and energy metabolism by transcriptionally co-regulating all 13 subunits of an important energy-generating enzyme, cytochrome c oxidase (COX), as well as critical subunits of excitatory NMDA receptors. AMPA receptors are another major class of excitatory glutamatergic receptors that mediate most of the fast excitatory synaptic transmission in the brain. They are heterotetrameric proteins composed of various combinations of GluA1-4 subunits, with GluA2 being the most common one. We have previously shown that GluA2 (Gria2) is transcriptionally regulated by nuclear respiratory factor 1 (NRF-1) and specificity protein 4 (Sp4), which also regulate all subunits of COX. However, it was not known if NRF-2 also couples neuronal activity and energy metabolism by regulating subunits of the AMPA receptors. By means of multiple approaches, including electrophoretic mobility shift and supershift assays, chromatin immunoprecipitation, promoter mutations, real-time quantitative PCR, and western blot analysis, NRF-2 was found to functionally regulate the expression of Gria2, but not of Gria1, Gria3, or Gria4 genes in neurons. By regulating the GluA2 subunit of the AMPA receptor, NRF-2 couples energy metabolism and neuronal activity at the transcriptional level through a concurrent and parallel mechanism with NRF-1 and Sp4.

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Distribution and targets of the relaxin‐3 innervation of the septal area in the rat

Olucha-Bordonau¹,

Otero-García²,

Sánchez-Pérez³

et al. 2012

J of Comparative Neurology

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Neural tracing studies have revealed that the rat medial and lateral septum are targeted by ascending projections from the nucleus incertus, a population of tegmental GABA neurons. These neurons express the relaxin‐family peptide, relaxin‐3, and pharmacological modulation of relaxin‐3 receptors in medial septum alters hippocampal theta rhythm and spatial memory. In an effort to better understand the basis of these interactions, we have characterized the distribution of relaxin‐3 fibers/terminals in relation to different septal neuron populations identified using established protein markers. Dense relaxin‐3 fiber plexuses were observed in regions of medial septum containing hippocampal‐projecting choline acetyltransferase (ChAT)‐, neuronal nitric oxide synthase (nNOS)‐, and parvalbumin (PV)‐positive neurons. In lateral septum (LS), relaxin‐3 fibers were concentrated in the ventrolateral nucleus of rostral LS and the ventral nucleus of caudal LS, with sparse labeling in the dorsolateral and medial nuclei of rostral LS, dorsal nucleus of caudal LS, and ventral portion nuclei. Relaxin‐3 fibers were also observed in the septofimbrial and triangular septal nuclei. In the medial septum, we observed relaxin‐3‐immunoreactive contacts with ChAT‐, PV‐, and glutamate decarboxylase‐67‐positive neurons that projected to hippocampus, and contacts between relaxin‐3 terminals and calbindin‐ and calretinin‐positive neurons. Relaxin‐3 colocalized with synaptophysin in nerve terminals in all septal areas, and ultrastructural analysis revealed these terminals were symmetrical and contacted spines, somata, dendritic shafts, and occasionally other axonal terminals. These data predict that this GABA/peptidergic projection modulates septohippocampal activity and hippocampal theta rhythm related to exploratory navigation, defensive and ingestive behaviors, and responses to neurogenic stressors. J. Comp. Neurol. 520:1903–1939, 2012. © 2011 Wiley Periodicals, Inc.

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Transcriptional coupling of synaptic transmission and energy metabolism: Role of nuclear respiratory factor 1 in co-regulating neuronal nitric oxide synthase and cytochrome c oxidase genes in neurons

Cited by 28 publications

References 51 publications

The Obligatory Intestinal Folate Transporter PCFT (SLC46A1) Is Regulated by Nuclear Respiratory Factor 1

The Obligatory Intestinal Folate Transporter PCFT (SLC46A1) Is Regulated by Nuclear Respiratory Factor 1

Nuclear respiratory factor 2 regulates the transcription of AMPA receptor subunit GluA2 (Gria2)

Distribution and targets of the relaxin‐3 innervation of the septal area in the rat

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