A brain-specific SGK1 splice isoform regulates expression of ASIC1 in neurons

Arteaga, Marı́a Francisca; Ćorić, Tatjana; Straub, Christoph; Canessa, Cecilia M.

doi:10.1073/pnas.0800958105

Cited by 53 publications

(72 citation statements)

References 34 publications

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“…Our results show that GR-responsive isoforms of Sgk1 are confined to astrocytes. The observation that Sgk1-002 is expressed in neurons, but not regulated by morphine or dexamethasone, is consistent with previous data (Arteaga et al, 2008). Although several other transcriptional variants were expressed in neurons and astrocytes, only two of them-Sgk1-003 and Sgk1-001-responded to GR activation, and their induction was restricted to astrocytes.…”

Section: Regulation Of Sgk1 Expression In Neural Cellssupporting

confidence: 92%

“…In particular, the specific neuronal roles of SGK1 in the CNS stress response (Yuen et al, 2010) and learning and memory (von Hertzen and Giese, 2005) were suggested. Few transcriptional variants of Sgk1 exist (Simon et al, 2007;Arteaga et al, 2008, Fig. 4A), and although one was described as neuron-specific (Sgk1-002; Arteaga et al, 2008), nothing was previously known about transcriptional regulation of Sgk1 in astrocytes.…”

Section: The Effects Of Morphine and Dexamethasonementioning

confidence: 99%

“…Few transcriptional variants of Sgk1 exist (Simon et al, 2007;Arteaga et al, 2008, Fig. 4A), and although one was described as neuron-specific (Sgk1-002; Arteaga et al, 2008), nothing was previously known about transcriptional regulation of Sgk1 in astrocytes. To elucidate that issue, we investigated the distribution and regulation of individual Sgk1 transcripts in vitro and in vivo.…”

Section: The Effects Of Morphine and Dexamethasonementioning

confidence: 99%

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Astrocytes are a neural target of morphine action via glucocorticoid receptor‐dependent signaling

Ślęzak

Korostyński

Gieryk

et al. 2013

Glia

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Chronic opioid use leads to the structural reorganization of neuronal networks, involving genetic reprogramming in neurons and glial cells. Our previous in vivo studies have revealed that a significant fraction of the morphine-induced alterations to the striatal transcriptome included glucocorticoid (GC) receptor (GR)-dependent genes. Additional analyses suggested glial cells to be the locus of these changes. In the current study, we aimed to differentiate the direct transcriptional effects of morphine and a GR agonist on primary striatal neurons and astrocytes. Whole-genome transcriptional profiling revealed that while morphine had no significant effect on gene expression in both cell types, dexamethasone significantly altered the transcriptional profile in astrocytes but not neurons. We obtained a complete dataset of genes undergoing the regulation, which includes genes related to glucose metabolism (Pdk4), circadian activity (Per1) and cell differentiation (Sox2). There was also an overlap between morphine-induced transcripts in striatum and GR-dependent transcripts in cultured astrocytes. We further analyzed the regulation of expression of one gene belonging to both groups, serum and GC regulated kinase 1 (Sgk1). We identified two transcriptional variants of Sgk1 that displayed selective GR-dependent upregulation in cultured astrocytes but not neurons. Moreover, these variants were the only two that were found to be upregulated in vivo by morphine in a GR-dependent fashion. Our data suggest that the morphine-induced, GR-dependent component of transcriptome alterations in the striatum is confined to astrocytes. Identification of this mechanism opens new directions for research on the role of astrocytes in the central effects of opioids. V V C 2013 Wiley Periodicals, Inc.

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Section: Regulation Of Sgk1 Expression In Neural Cellssupporting

confidence: 92%

Section: The Effects Of Morphine and Dexamethasonementioning

confidence: 99%

Section: The Effects Of Morphine and Dexamethasonementioning

confidence: 99%

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Astrocytes are a neural target of morphine action via glucocorticoid receptor‐dependent signaling

Ślęzak

Korostyński

Gieryk

et al. 2013

Glia

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“…Interestingly, a recent study by Arteaga et al (20) reported that SGK1.1, a brain-specific splice isoform of SGK1, decreases expression of ASIC1a at the cell surface. It would be speculative yet interesting to find out whether insulin-mediated ASIC1a regulation occurs through the SGK1.1 signaling pathway in neuronal cells, because SGK1.1 is not regulated by glucocorticoid in the brain (20).…”

Section: Discussionmentioning

confidence: 99%

Activation of Acid-sensing Ion Channel 1a (ASIC1a) by Surface Trafficking

Chai

Branigan

et al. 2010

Journal of Biological Chemistry

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Acid-sensing ion channels (ASICs) are voltage-independent Na ؉ channels activated by extracellular protons. ASIC1a is expressed in neurons in mammalian brain and is implicated in long term potentiation of synaptic transmission that contributes to learning and memory. In ischemic brain injury, however, activation of this Ca 2؉ -permeable channel plays a critical role in acidosis-mediated, glutamate-independent, Ca 2؉ toxicity. We report here the identification of insulin as a regulator of ASIC1a surface expression. In modeled ischemia using Chinese hamster ovary cells, serum depletion caused a significant increase in ASIC1a surface expression that resulted in the potentiation of ASIC1a activity. Among the components of serum, insulin was identified as the key factor that maintains a low level of ASIC1a on the plasma membrane. Neurons subjected to insulin depletion increased surface expression of ASIC1a with resultant potentiation of ASIC1a currents. Intracellularly, ASIC1a is predominantly localized to the endoplasmic reticulum in Chinese hamster ovary cells, and this intracellular localization is also observed in neurons. Under conditions of serum or insulin depletion, the intracellular ASIC1a is translocated to the cell surface, increasing the surface expression level. These results reveal an important trafficking mechanism of ASIC1a that is relevant to both the normal physiology and the pathological activity of this channel.Acid-sensing ion channels belong to the epithelial sodium channel and degenerin family of ion channels and primarily transport Na ϩ into cells. ASICs 2 are activated by the presence of extracellular protons, which serve as ligands for these channels. So far six isoforms of ASICs (ASIC1a, 1b, 2a, 2b, 3, and 4) have been found in the mammalian central and peripheral nervous system. ASIC1a is expressed in various regions of brain including hippocampus, cerebral cortex, cerebellum, and amygdala (1-3). The role of ASIC1a in brain function is well characterized, in particular by electrophysiological and behavioral studies of ASIC1a knock-out (ASIC1aH ϩ -evoked currents are involved in synaptic transmission that contributes to important normal brain functions such as learning and memory in hippocampus and fear-related behaviors in the amygdala (3-5). Like other ASIC isoforms, the amino acid sequence of ASIC1a reveals a structure highly conserved among the epithelial sodium channel family (6). The crystal structure of a truncated chicken ASIC1a channel determined that this two-transmembrane protein is assembled as a trimer (7). Cerebral neurons express native ASIC1a as an assembly of homomultimers as well as heteromultimers in association with ASIC2a (8). Although ASIC1a and ASIC2a share high homology in their amino acid sequences, these proton-activated channels exhibit distinct sensitivity to extracellular pH. ASIC1a is more sensitive to changes in extracellular proton levels than ASIC2a and thus activates at a higher pH (pH of halfmaximal channel activation pH 0.5 ϭ 6.2), whereas ASIC2a activate...

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“…We and others previously reported that a highly conserved alternate transcript of Sgk1, termed Sgk1_v2, encodes NH 2 -terminal variant Sgk1 isoform, Sgk1_i2 (Sgk1.1), that is more stable and increases the activity of a number of cation channels of the ENaC/degenerin family (1,20,27). Although expressed in the CD, this isoform is not regulated by corticosteroids and its relevance in aldosterone-regulated distal nephron Na ϩ transport may be limited.…”

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confidence: 99%

A regulated NH₂-terminal Sgk1 variant with enhanced function is expressed in the collecting duct

Raikwar

Liu

Thomas

2012

American Journal of Physiology-Renal Physiology

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A brain-specific SGK1 splice isoform regulates expression of ASIC1 in neurons

Cited by 53 publications

References 34 publications

Astrocytes are a neural target of morphine action via glucocorticoid receptor‐dependent signaling

Astrocytes are a neural target of morphine action via glucocorticoid receptor‐dependent signaling

Activation of Acid-sensing Ion Channel 1a (ASIC1a) by Surface Trafficking

A regulated NH₂-terminal Sgk1 variant with enhanced function is expressed in the collecting duct

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A brain-specific SGK1 splice isoform regulates expression of ASIC1 in neurons

Cited by 53 publications

References 34 publications

Astrocytes are a neural target of morphine action via glucocorticoid receptor‐dependent signaling

Astrocytes are a neural target of morphine action via glucocorticoid receptor‐dependent signaling

Activation of Acid-sensing Ion Channel 1a (ASIC1a) by Surface Trafficking

A regulated NH2-terminal Sgk1 variant with enhanced function is expressed in the collecting duct

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A regulated NH₂-terminal Sgk1 variant with enhanced function is expressed in the collecting duct