Inhibition of oxidative metabolism increases persistent sodium current in rat CA1 hippocampal neurons

Hammarström, Anne; Gage, Peter W.

doi:10.1111/j.1469-7793.1998.735bj.x

Cited by 105 publications

(75 citation statements)

References 26 publications

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“…The mechanism of ischemic Na i overload is not yet fully understood. It has been speculated that the noninactivating Na ϩ current (also called sustained or persistent Na ϩ current) is responsible for Na i overload under ischemic conditions (7,11). Recent studies (24) demonstrated that the Na ϩ channel represents a target molecule for PP1.…”

Section: Discussionmentioning

confidence: 99%

Role of protein phosphatases in hypoxic preconditioning

Ladilov

Maxeiner

Wolf

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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To find a protein kinase C (PKC)-independent preconditioning mechanism, hypoxic preconditioning (HP; i.e., 10-min anoxia and 10-min reoxygenation) was applied to isolated rat hearts before 60-min global ischemia. HP led to improved recovery of developed pressure and reduced end-diastolic pressure in the left ventricle during reperfusion. Protection was unaffected by the PKC inhibitor bisindolylmaleimide (BIM; 1 mol/l). It was abolished by the inhibitor of protein phosphatases 1 and 2A cantharidin (20 or 5 mol/l) and partially enhanced by the inhibitor of protein phosphatase 2A okadaic acid (5 nmol/l). In adult rat cardiomyocytes treated with BIM and exposed to 60-min simulated ischemia (anoxia, extracellular pH 6.4), HP led to attenuation of anoxic Na ϩ /Ca 2ϩ overload and of hypercontracture, which developed on reoxygenation. This protection was prevented by treatment with cantharidin but not with okadaic acid. In conclusion, HP exerts PKC-independent protection on ischemic-reperfused rat hearts and cardiomyocytes. Protein phosphatase 1 seems a mediator of this protective mechanism. cellular calcium; heart function; ischemia; reperfusion SEVERAL STUDIES (18,25,32) have demonstrated that protection of the myocardium against ischemia-reperfusion injury caused by a brief preceding ischemia (ischemic preconditioning) is due to the release and accumulation of endogenous mediators, such as adenosine or noradrenaline, during ischemic preconditioning and a subsequent activation of protein kinase C (PKC). There are, however, data (20,23,27) indicating that protection by ischemic preconditioning can also be achieved independent of PKC activation. The mechanism of this PKC-independent protection could not be explained. Brief periods of hypoxia, i.e., hypoxic preconditioning (HP), which do not allow accumulation of ischemic mediators, can also provide protection against ischemia-reperfusion injury (17,19,30,32). Previous studies (14, 26) of isolated hearts demonstrated that protection induced by HP does not involve the activation of adenosine receptors or G i proteins, suggesting a protective signaling different from well-known mechanisms of ischemic preconditioning. A protective role of PKC in HP was suggested for cultured embryonic cardiac myocytes (6, 29), but this was not demonstrated in adult cardiac myocytes or the adult whole heart. In general, the mechanisms of HP-induced protection are still not fully understood. For the present study, we hypothesized that HP leads to protection due to a PKC-independent mechanism. We (1) tested whether protection induced by HP is PKC independent and (3) which other type of signaling is responsible for HPinduced protection. Motivated by reports (2, 3) that inhibitors of these protein phosphatases (PP) can imitate ischemic preconditioning in some experimental models, we focused our study on the role of serine threonine PP1 and PP2A.We used the experimental model of isolated Langendorff-perfused rat hearts exposed to 60 min of global ischemia and 60 min of reperfusion. To test for im...

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Section: Discussionmentioning

confidence: 99%

Role of protein phosphatases in hypoxic preconditioning

Ladilov

Maxeiner

Wolf

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…However, a loss of membrane potential or massive Ca 2+ influx did not occur in these cells even during prolonged CN − induced chemical anoxia (Müller and Ballanyi, 2003). CN − has also been shown to increase voltage-dependent Na + currents in CA1 hippocampal cells (Hammarström and Gage, 1998).…”

Section: 14mentioning

confidence: 99%

Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration

Foster

Galeffi

Gerich

et al. 2006

Progress in Neurobiology

166

135

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Mitochondria are critical for cellular ATP production; however, recent studies suggest that these organelles fulfill a much broader range of tasks. For example, they are involved in the regulation of cytosolic Ca 2+ levels, intracellular pH and apoptosis, and are the major source of reactive oxygen species (ROS). Various reactive molecules that originate from mitochondria, such as ROS, are critical in pathological events, such as ischemia, as well as in physiological events such as long-term potentiation, neuronal-vascular coupling and neuronal-glial interactions. Due to their key roles in the regulation of several cellular functions, the dysfunction of mitochondria may be critical in various brain disorders. There has been increasing interest in the development of tools that modulate mitochondrial function, and the refinement of techniques that allow for real time monitoring of mitochondria, particularly within their intact cellular environment. Innovative imaging techniques are especially powerful since they allow for mitochondrial visualization at high resolution, tracking of mitochondrial structures and optical real time monitoring of parameters of mitochondrial function. Among the techniques discussed are the uses of classic imaging techniques such as rhodamine-123, the highly advanced semi-conductor nanoparticles (quantum dots), and wide field microscopy as well as high-resolution multi-photon imaging. We have highlighted the use of these techniques to study mitochondrial function in brain tissue and have included studies from our laboratories in which these techniques have been successfully applied.

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“…It is decreased in parallel with I NaT by activation of muscarinic acetylcholine receptors and consequent phosphorylation by protein kinase C in hippocampal neurons (Cantrell et al, 1996). It is increased by hypoxia and nitric oxide in hippocampal neurons (Hammarstrom and Gage, 1998, 1999, 2000. In addition, I NaP is increased when G-protein ␤␥ subunits are coexpressed with Na v 1.2 channels .…”

Section: Introductionmentioning

confidence: 99%

Molecular Determinants for Modulation of Persistent Sodium Current by G-Protein βγ Subunits

Mantegazza¹,

Yu²,

Powell³

et al. 2005

J. Neurosci.

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Voltage-gated sodium channels are responsible for the upstroke of the action potential in most excitable cells, and their fast inactivation is essential for controlling electrical signaling. In addition, a noninactivating, persistent component of sodium current, I NaP , has been implicated in integrative functions of neurons including threshold for firing, neuronal bursting, and signal integration. G-protein ␤␥ subunits increase I NaP , but the sodium channel subtypes that conduct I NaP and the target site(s) on the sodium channel molecule required for modulation by G␤␥ are poorly defined. Here, we show that I NaP conducted by Na v 1.1 and Na v 1.2 channels (Na v 1.1 Ͼ Na v 1.2) is modulated by G␤␥; Na v 1.4 and Na v 1.5 channels produce smaller I NaP that is not regulated by G␤␥. These qualitative differences in modulation by G␤␥ are determined by the transmembrane body of the sodium channels rather than their cytoplasmic C-terminal domains, which have been implicated previously in modulation by G␤␥. However, the C-terminal domains determine the quantitative extent of modulation of Na v 1.2 channels by G␤␥. Studies of chimeric and truncated Na v 1.2 channels identify molecular determinants that affect modulation of I NaP located between amino acid residue 1890 and the C terminus at residue 2005. The last 28 amino acid residues of the C terminus are sufficient to support modulation by G␤␥ when attached to the proximal C-terminal domain. Our results further define the sodium channel subtypes that generate I NaP and identify crucial molecular determinants in the C-terminal domain required for modulation by G␤␥ when attached to the transmembrane body of a responsive sodium channel.

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Inhibition of oxidative metabolism increases persistent sodium current in rat CA1 hippocampal neurons

Cited by 105 publications

References 26 publications

Role of protein phosphatases in hypoxic preconditioning

Role of protein phosphatases in hypoxic preconditioning

Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration

Molecular Determinants for Modulation of Persistent Sodium Current by G-Protein βγ Subunits

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