Activation of AMP-activated Protein Kinase Regulates Hippocampal Neuronal pH by Recruiting Na+/H+ Exchanger NHE5 to the Cell Surface

Jinadasa, Tushare; Szabó, Elöd Z.; Numata, Masayuki; Orlowski, John

doi:10.1074/jbc.m114.555284

Cited by 20 publications

(10 citation statements)

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“…Thus, we can speculate that the hydrophobic character of NHE1-binding pocket, stronger than its counterpart in NHE5, may be responsible of more stable binding interactions with the hydrophobic moiety (the isopropyl -aromatic portion) of cariporide. This hypothesis is consistent with evidence from the work by Jinadasa et al (2014) that, in AP-1 (NHE-deficient) cells, stably transfected with NHE1, after acid load with NH 4 Cl, the intracellular pH recover was completely blocked at 1-10 µM concentration of cariporide while substantially higher concentrations of cariporide (500-1000 µM) were required to block pH i recovery in AP-1 NHE5-expressing cells. Taken together, all the above considerations suggest that, in our study, the component of Na + -dependent H + efflux was more likely due to NHE1 activity rather than activity from other isoforms.…”

Section: Discussionsupporting

confidence: 91%

Effect of cariporide on ram sperm pH regulation and motility: possible role of NHE1

et al. 2018

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Sperm motility, a feature essential for fertilization, is influenced by intracellular pH (pH) homeostasis. Several mechanisms are involved in pH regulation, among which sodium-hydrogen exchangers (NHEs), a family of integral transmembrane proteins that catalyze the exchange of Na for H across lipid bilayers. A preliminary characterization of NHE activity and kinetic parameters, followed by analysis of the expression and localization of the protein in ram spermatozoa was performed. NHE activity showed an apparent for external Na of 17.61 mM. Immunoblotting revealed a molecular mass of 85 kDa. Immunolocalization pattern showed some species-specific aspects, such as positive labeling at the equatorial region of the sperm head. Cariporide, a selective NHE1 inhibitor, significantly reduced pH recovery (85%). Similarly, exposure to cariporide significantly inhibited different motility parameters, including those related to sperm capacitation. fertilization (IVF) was not affected by cariporide, possibly due to the non-dramatic, although significant, drop in motility and velocity parameters or due to prolonged exposure during IVF, which may have caused progressive loss of its inhibitory effect. In conclusion, this is the first study documenting, in a large animal model (sheep) of well-known translational relevance, a direct functional role of NHE on sperm pH and motility. The postulated specificity of cariporide toward isoform 1 of the Na/H exchanger seems to suggest that NHE1 may contribute to the observed effects on sperm cell functionality.

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Section: Discussionsupporting

confidence: 91%

Effect of cariporide on ram sperm pH regulation and motility: possible role of NHE1

et al. 2018

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“…Inhibition of AMPK by Compound C (a classical AMPK antagonist) exacerbates OGD-induced neuronal injury, while treatment with AICAR reverses the effects above 52 . Antimycin A, a mitochondrial respiratory inhibitor in oxidative phosphorylation, is able to maintain intracellular pH homeostasis of the hippocampal neurons by recruiting Na + /H + exchanger 5 (NHE5) to the cytomembrane, whereas these effects are effectively eliminated by Compound C, the NHE inhibitor HOE694, or AMPK mutation 53 , 54 . Together, upstream agonists/activators are necessary for the activation of AMPK and to guarantee its protective effects during metabolic stress.…”

Section: General Aspects Regarding Ampkmentioning

confidence: 99%

AMPK: Potential Therapeutic Target for Ischemic Stroke

et al. 2018

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5'-AMP-activated protein kinase (AMPK), a member of the serine/threonine (Ser/Thr) kinase group, is universally distributed in various cells and organs. It is a significant endogenous defensive molecule that responds to harmful stimuli, such as cerebral ischemia, cerebral hemorrhage, and, neurodegenerative diseases (NDD). Cerebral ischemia, which results from insufficient blood flow or the blockage of blood vessels, is a major cause of ischemic stroke. Ischemic stroke has received increased attention due to its '3H' effects, namely high mortality, high morbidity, and high disability. Numerous studies have revealed that activation of AMPK plays a protective role in the brain, whereas its action in ischemic stroke remains elusive and poorly understood. Based on existing evidence, we introduce the basic structure, upstream regulators, and biological roles of AMPK. Second, we analyze the relationship between AMPK and the neurovascular unit (NVU). Third, the actions of AMPK in different phases of ischemia and current therapeutic methods are discussed. Finally, we evaluate existing controversy and provide a detailed analysis, followed by ethical issues, potential directions, and further prospects of AMPK. The information complied here may aid in clinical and basic research of AMPK, which may be a potent drug candidate for ischemic stroke treatment in the future.

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“…Neuronal excitability and neurotransmission are metabolically powerful activities that induce excessive changes in intracellular pH ( Chesler and Kaila, 1992 ). These pH alterations further regulate electrical activity by regulating the conductance of various pH-sensitive neurotransmitters-, voltage-, and proton-gated ion channels ( Jinadasa et al ., 2014 ). The influence of intracellular and extracellular pH oscillation on neuronal excitability is well established and partly attributed to H + sensitivity of neurotransmitter receptors and voltage-gated ion channels ( Tang et al ., 1990 ; Rocha et al ., 2008 ).…”

Section: Introductionmentioning

confidence: 99%

Sustained Intracellular Acidosis Triggers the Na⁺/H⁺Exchager-1 Activation in Glutamate Excitotoxicity

Lee

2017

Biomolecules & Therapeutics

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The Na+/H+ exchanger-1 (NHE-1) is a ubiquitously expressed pH-regulatory membrane protein that functions in the brain, heart, and other organs. It is increased by intracellular acidosis through the interaction of intracellular H+ with an allosteric modifier site in the transport domain. In the previous study, we reported that glutamate-induced NHE-1 phosphorylation mediated by activation of protein kinase C-β (PKC-β) in cultured neuron cells via extracellular signal-regulated kinases (ERK)/p90 ribosomal s6 kinases (p90RSK) pathway results in NHE-1 activation. However, whether glutamate stimulates NHE-1 activity solely by the allosteric mechanism remains elusive. Cultured primary cortical neuronal cells were subjected to intracellular acidosis by exposure to 100 μM glutamate or 20 mM NH4Cl. After the desired duration of intracellular acidosis, the phosphorylation and activation of PKC-β, ERK1/2 and p90RSK were determined by Western blotting. We investigated whether the duration of intracellular acidosis is controlled by glutamate exposure time. The NHE-1 activation increased while intracellular acidosis sustained for >3 min. To determine if sustained intracellular acidosis induced NHE-1 phosphorylation, we examined phosphorylation of NHE-1 induced by intracellular acidosis by transient exposure to NH4Cl. Sustained intracellular acidosis led to activation and phosphorylation of NHE-1. In addition, sustained intracellular acidosis also activated the PKC-β, ERK1/2, and p90RSK in neuronal cells. We conclude that glutamate stimulates NHE-1 activity through sustained intracellular acidosis, which mediates NHE-1 phosphorylation regulated by PKC-β/ERK1/2/p90RSK pathway in neuronal cells.

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Activation of AMP-activated Protein Kinase Regulates Hippocampal Neuronal pH by Recruiting Na+/H+ Exchanger NHE5 to the Cell Surface

Cited by 20 publications

References 98 publications

Effect of cariporide on ram sperm pH regulation and motility: possible role of NHE1

Effect of cariporide on ram sperm pH regulation and motility: possible role of NHE1

AMPK: Potential Therapeutic Target for Ischemic Stroke

Sustained Intracellular Acidosis Triggers the Na⁺/H⁺Exchager-1 Activation in Glutamate Excitotoxicity

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Activation of AMP-activated Protein Kinase Regulates Hippocampal Neuronal pH by Recruiting Na+/H+ Exchanger NHE5 to the Cell Surface

Cited by 20 publications

References 98 publications

Effect of cariporide on ram sperm pH regulation and motility: possible role of NHE1

Effect of cariporide on ram sperm pH regulation and motility: possible role of NHE1

AMPK: Potential Therapeutic Target for Ischemic Stroke

Sustained Intracellular Acidosis Triggers the Na+/H+Exchager-1 Activation in Glutamate Excitotoxicity

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Product

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Sustained Intracellular Acidosis Triggers the Na⁺/H⁺Exchager-1 Activation in Glutamate Excitotoxicity