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Regulation of N a + / K + ‐ ATP ase by neuron‐specific transcription factor S p4: implication in the tight coupling of energy production, neuronal activity and energy consumption in neurons
Author(s) -
Johar Kaid,
Priya Anusha,
WongRiley Margaret T. T.
Publication year - 2014
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.12415
Subject(s) - chromatin immunoprecipitation , biology , neuron , transcription factor , microbiology and biotechnology , gene silencing , gene expression , biochemistry , promoter , gene , neuroscience
A major source of energy demand in neurons is the N a + / K + ‐ ATP ase pump that restores the ionic gradient across the plasma membrane subsequent to depolarizing neuronal activity. The energy comes primarily from mitochondrial oxidative metabolism, of which cytochrome c oxidase ( COX ) is a key enzyme. Recently, we found that all 13 subunits of COX are regulated by specificity ( S p) factors, and that the neuron‐specific S p4, but not S p1 or S p3, regulates the expression of key glutamatergic receptor subunits as well. The present study sought to test our hypothesis that S p4 also regulates N a + / K + ‐ ATP ase subunit genes in neurons. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, chromatin immunoprecipitation, promoter mutational analysis, over‐expression, and RNA interference studies, we found that S p4, with minor contributions from Sp1 and Sp3, functionally regulate the A tp1a1, A tp1a3 , and A tp1b1 subunit genes of N a + / K + ‐ ATP ase in neurons. Transcripts of all three genes were up‐regulated by depolarizing KC l stimulation and down‐regulated by the impulse blocker tetrodotoxin ( TTX ), indicating that their expression was activity‐dependent. Silencing of S p4 blocked the up‐regulation of these genes induced by KC l, whereas over‐expression of S p4 rescued them from TTX ‐induced suppression. The effect of silencing or over‐expressing S p4 on primary neurons was much greater than those of S p1 or S p3. The binding sites of S p factors on these genes are conserved among mice, rats and humans. Thus, S p4 plays an important role in the transcriptional coupling of energy generation and energy consumption in neurons.