scholarly journals Down-Regulation of the Na+,Cl- Coupled Creatine Transporter CreaT (SLC6A8) by Glycogen Synthase Kinase GSK3ß

2016 ◽  
Vol 40 (5) ◽  
pp. 1231-1238 ◽  
Author(s):  
Myriam Fezai ◽  
Mohamed Jemaà ◽  
Hajar Fakhri ◽  
Hong Chen ◽  
Bhaeldin Elsir ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Xenopus Laevis Oocytes ◽  
Induced Current ◽  
Wild Type ◽  
Creatine Transporter ◽  
Electrode Voltage ◽  
Creatine Transport ◽  
The Brain ◽  
Current Kinetic

Background: The Na+,Cl- coupled creatine transporter CreaT (SLC6A8) is expressed in a variety of tissues including the brain. Genetic defects of CreaT lead to mental retardation with seizures. The present study explored the regulation of CreaT by the ubiquitously expressed glycogen synthase kinase GSK3ß, which contributes to the regulation of neuroexcitation. GSK3ß is phosphorylated and thus inhibited by PKB/Akt. Moreover, GSK3ß is inhibited by the antidepressant lithium. The present study thus further tested for the effects of PKB/Akt and of lithium. Methods: CreaT was expressed in Xenopus laevis oocytes with or without wild-type GSK3ß or inactive K85RGSK3ß. CreaT and GSK3ß were further expressed without and with additional expression of wild type PKB/Akt. Creatine transport in those oocytes was quantified utilizing dual electrode voltage clamp. Results: Electrogenic creatine transport was observed in CreaT expressing oocytes but not in water-injected oocytes. In CreaT expressing oocytes, co-expression of GSK3ß but not of K85RGSK3ß, resulted in a significant decrease of creatine induced current. Kinetic analysis revealed that GSK3ß significantly decreased the maximal creatine transport rate. Exposure of CreaT and GSK3ß expressing oocytes for 24 hours to Lithium was followed by a significant increase of the creatine induced current. The effect of GSK3ß on CreaT was abolished by co-expression of PKB/Akt. Conclusion: GSK3ß down-regulates the creatine transporter CreaT, an effect reversed by treatment with the antidepressant Lithium and by co-expression of PKB/Akt.

scholarly journals Up-Regulation of the Large-Conductance Ca2+-Activated K+ Channel by Glycogen Synthase Kinase GSK3β

2016 ◽  
Vol 39 (3) ◽  
pp. 1031-1039 ◽  
Author(s):  
Myriam Fezai ◽  
Musaab Ahmed ◽  
Zohreh Hosseinzadeh ◽  
Florian Lang
Keyword(s):  
Cell Volume ◽  
Glycogen Synthase ◽  
Negative Control ◽  
Bk Channels ◽  
Bk Channel ◽  
Glycogen Synthase Kinase ◽  
K Channel ◽  
Xenopus Laevis Oocytes ◽  
Channel Activity ◽  
Wild Type

Background/Aims: The pleotropic functions of the large conductance Ca2+-activated K+ channels (maxi K+ channel or BK channels) include regulation of neuronal excitation and cell volume. Kinases participating in those functions include the glycogen synthase kinase GSK3 ß which is under negative control of protein kinase B (PKB/Akt). GSK3ß is inhibited by the antidepressant Lithium. The present study thus explored whether GSK3ß modifies the activity of BK channels. Methods: cRNA encoding the Ca2+ insensitive BK channel mutant BKM513I+Δ899-903 was injected into Xenopus laevis oocytes without or with additional injection of cRNA encoding wild-type GSK3ß, inactive K85RGSK3ß, or wild-type GSK3ß with wild-type PKB. K+ channel activity was measured utilizing dual electrode voltage clamp. Results: BK channel activity in BKM513I+Δ899-903 expressing oocytes was significantly increased by co-expression of GSK3ß, but not by co-expression of K85RGSK3ß. The effect of wild type GSK3ß was abrogated by additional co-expression of wild-type PKB and by 24 hours incubation with Lithium (1 mM). Disruption of channel insertion into the cell membrane by brefeldin A (5 µM) was followed by a decline of the current to a similar extent in oocytes expressing BK and GSK3ß and in oocytes expressing BK alone. Conclusion: GSK3ß may up-regulate BK channels, an effect disrupted by Lithium or additional expression of PKB and possibly participating in the regulation of cell volume and excitability.

scholarly journals Up-Regulation of Excitatory Amino Acid Transporters EAAT3 and EAAT4 by Lithium Sensitive Glycogen Synthase Kinase GSK3ß

2016 ◽  
Vol 40 (5) ◽  
pp. 1252-1260 ◽  
Author(s):  
Abeer Abousaab ◽  
Florian Lang
Keyword(s):  
Amino Acid ◽  
Xenopus Oocytes ◽  
Excitatory Amino Acid ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Amino Acid Transporters ◽  
Wild Type ◽  
Neuronal Function ◽  
Excitatory Amino Acid Transporters ◽  
Electrode Voltage

Background: Cellular uptake of glutamate by the excitatory amino-acid transporters (EAATs) decreases excitation and thus participates in the regulation of neuroexcitability. Kinases impacting on neuronal function include Lithium-sensitive glycogen synthase kinase GSK3ß. The present study thus explored whether the activities of EAAT3 and/or EAAT4 isoforms are sensitive to GSK3ß. Methods: cRNA encoding wild type EAAT3 (SLC1A1) or EAAT4 (SLC1A6) was injected into Xenopus oocytes without or with additional injection of cRNA encoding wild type GSK3ß or the inactive mutant K85AGSK3ß. Dual electrode voltage clamp was performed in order to determine glutamate-induced current (IEAAT). Results: Appreciable IEAAT was observed in EAAT3 or EAAT4 expressing but not in water injected oocytes. IEAAT was significantly increased by coexpression of GSK3ß but not by coexpression of K85AGSK3ß. Coexpression of GSK3ß increased significantly the maximal IEAAT in EAAT3 or EAAT4 expressing oocytes, without significantly modifying apparent affinity of the carriers. Lithium (1 mM) exposure for 24 hours decreased IEAAT in EAAT3 and GSK3ß expressing oocytes to values similar to IEAAT in oocytes expressing EAAT3 alone. Lithium did not significantly modify IEAAT in oocytes expressing EAAT3 without GSK3ß. Conclusions: Lithium-sensitive GSK3ß is a powerful regulator of excitatory amino acid transporters EAAT3 and EAAT4.

Regulation of intestinal phosphate cotransporter NaPi IIb by ubiquitin ligase Nedd4–2 and by serum- and glucocorticoid-dependent kinase 1

2004 ◽  
Vol 287 (1) ◽  
pp. G143-G150 ◽  
Author(s):  
M. Palmada ◽  
M. Dieter ◽  
A. Speil ◽  
C. Böhmer ◽  
A. F. Mack ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Phosphate Transport ◽  
Transport Systems ◽  
Xenopus Laevis Oocytes ◽  
Intestinal Epithelial ◽  
Induced Current ◽  
Intestinal Function ◽  
Transport Activity ◽  
Wild Type ◽  
Subsequent Degradation

Serum and glucocorticoid-inducible kinase 1 (SGK1) is highly expressed in enterocytes. The significance of the kinase in regulation of intestinal function has, however, remained elusive. In Xenopus laevis oocytes, SGK1 stimulates the epithelial Na+ channel by phosphorylating the ubiquitin ligase Nedd4–2, which regulates channels by ubiquitination leading to subsequent degradation of the channel protein. Thus the present study has been performed to explore whether SGK1 regulates transport systems expressed in intestinal epithelial cells, specifically type IIb sodium-phosphate (Na+-Pi) cotransporter (NaPi IIb). Immunohistochemistry in human small intestine revealed SGK1 colocalization with Nedd4–2 in villus enterocytes. For functional analysis cRNA encoding NaPi IIb, the SGK isoforms and/or the Nedd4–2 were injected into X. laevis oocytes, and transport activity was quantified as the substrate-induced current ( IP). Exposure to 3 mM phosphate induces an IP in NaPi IIb-expressing oocytes. Coinjection of Nedd4–2, but not the catalytically inactive mutant C938SNedd4–2, significantly downregulates IP, whereas the coinjection of S422DSGK1 markedly stimulates IP and even fully reverses the effect of Nedd4–2 on IP. The effect of S422DSGK1 on NaPi IIb is mimicked by wild-type SGK3 but not by wild-type SGK2, constitutively active T308D,S473DPKB, or inactive K127NSGK1. Moreover, S422DSGK1 and SGK3 phosphorylate Nedd4–2. In conclusion, SGK1 stimulates the NaPi IIb, at least in part, by phosphorylating and thereby inhibiting Nedd4–2 binding to its target. Thus the present study reveals a novel signaling pathway in the regulation of intestinal phosphate transport, which may be important for regulation of phosphate balance.

scholarly journals Evidence that glycogen synthase kinase-3 isoforms have distinct substrate preference in the brain

2010 ◽  
Vol 115 (4) ◽  
pp. 974-983 ◽  
Author(s):  
Marc P. M. Soutar ◽  
Woo-Yang Kim ◽  
Ritchie Williamson ◽  
Mark Peggie ◽  
Charles James Hastie ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Substrate Preference ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
The Brain

scholarly journals Glycogen Synthase Kinase-3β: A Mediator of Inflammation in Alzheimer's Disease?

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Jari Koistinaho ◽  
Tarja Malm ◽  
Gundars Goldsteins
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
Immune Defense ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Normal Brain ◽  
Brain Functions ◽  
The Brain

Proliferation and activation of microglial cells is a neuropathological characteristic of brain injury and neurodegeneration, including Alzheimer's disease. Microglia act as the first and main form of immune defense in the nervous system. While the primary function of microglia is to survey and maintain the cellular environment optimal for neurons in the brain parenchyma by actively scavenging the brain for damaged brain cells and foreign proteins or particles, sustained activation of microglia may result in high production of proinflammatory mediators that disturb normal brain functions and even cause neuronal injury. Glycogen synthase kinase-3βhas been recently identified as a major regulator of immune system and mediates inflammatory responses in microglia. Glycogen synthase kinase-3βhas been extensively investigated in connection to tau and amyloidβtoxicity, whereas reports on the role of this enzyme in neuroinflammation in Alzheimer's disease are negligible. Here we review and discuss the role of glycogen synthase-3βin immune cells in the context of Alzheimer's disease pathology.

PI4KIIα phosphorylation by GSK3 directs vesicular trafficking to lysosomes

2014 ◽  
Vol 464 (1) ◽  
pp. 145-156 ◽  
Author(s):  
James W. Robinson ◽  
Iryna Leshchyns’ka ◽  
Hovik Farghaian ◽  
William E. Hughes ◽  
Vladimir Sytnyk ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Vesicular Trafficking ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Lipid Kinase ◽  
Phosphatidylinositol 4 ◽  
The Brain

Glycogen synthase kinase 3 (GSK3) regulates neurotransmission in the brain, but the substrates mediating this are unclear. In the present paper, we report the lipid kinase phosphatidylinositol 4-kinase II α (PI4KIIα) is a novel substrate of GSK3 that switches vesicular trafficking from secretory/recycling pathways to the lysosome in neurons.

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