Protein phosphatase 2A inhibition induces cerebellar long-term depression and declustering of synaptic AMPA receptor

Lavstsen, Thomas; Endo, Shogo; Sakai, Rieko; Harano, J.; Ito, Masao

doi:10.1073/pnas.0302914101

Cited by 66 publications

(57 citation statements)

References 51 publications

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“…18 Cell death may also be triggered by a shift in the balance of protein phosphorylation and dephosphorylation through the observed acute increase of phosphorylated 2IPP2A or by a dysregulation of ANX5, an early-stage apoptosis marker. 19,20 A decrease of PDCD5 protein may either be caused by acutely increased rates of apoptosis (protein depletion) or may be the result of a primary antiapoptotic effect. 21,22 Decreased levels of PEA-15 protein have been associated with astrocyte protection against TNF-induced apoptosis.…”

Section: Oxidative Stress Apoptosis and Growthmentioning

confidence: 99%

Acute and long-term proteome changes induced by oxidative stress in the developing brain

et al. 2005

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The developing mammalian brain experiences a period of rapid growth during which various otherwise innocuous environmental factors cause widespread apoptotic neuronal death. To gain insight into developmental events influenced by a premature exposure to high oxygen levels and identify proteins engaged in neurodegenerative and reparative processes, we analyzed mouse brain proteome changes at P7, P14 and P35 caused by an exposure to hyperoxia at P6. Changes detected in the brain proteome suggested that hyperoxia leads to oxidative stress and apoptotic neuronal death. These changes were consistent with results of histological and biochemical evaluation of the brains, which revealed widespread apoptotic neuronal death and increased levels of protein carbonyls. Furthermore, we detected changes in proteins involved in synaptic function, cell proliferation and formation of neuronal connections, suggesting interference of oxidative stress with these developmental events. These effects are age-dependent, as they did not occur in mice subjected to hyperoxia in adolescence.

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Section: Oxidative Stress Apoptosis and Growthmentioning

confidence: 99%

Acute and long-term proteome changes induced by oxidative stress in the developing brain

et al. 2005

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“…For example, protein phosphatase 2B (PP2B; also known as calcineurin) constrains intermediate-and long-term facilitation in Aplysia, likely via effects on mitogen-activated protein kinases (Sharma et al, 2003). Similarly, protein phosphatases constrain long-term potentiation and depression in rats Launey et al, 2004;Belmeguenai and Hansel, 2005;Tomita et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Okadaic Acid-Sensitive Protein Phosphatases Constrain Phrenic Long-Term Facilitation after Sustained Hypoxia

Wilkerson¹,

Satriotomo²,

Baker-Herman³

et al. 2008

J. Neurosci.

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Phrenic long-term facilitation (pLTF) is a serotonin-dependent form of pattern-sensitive respiratory plasticity induced by intermittent hypoxia (IH), but not sustained hypoxia (SH). The mechanism(s) underlying pLTF pattern sensitivity are unknown. SH and IH may differentially regulate serine/threonine protein phosphatase activity, thereby inhibiting relevant protein phosphatases uniquely during IH and conferring pattern sensitivity to pLTF. We hypothesized that spinal protein phosphatase inhibition would relieve this braking action of protein phosphatases, thereby revealing pLTF after SH. Anesthetized rats received intrathecal (C4) okadaic acid (25 nM) before SH (25 min, 11% O 2 ). Unlike (vehicle) control rats, SH induced a significant pLTF in okadaic acid-treated rats that was indistinguishable from rats exposed to IH (three 5 min episodes, 11% O 2 ). IH and SH with okadaic acid may elicit pLTF by similar, serotonin-dependent mechanisms, because intravenous methysergide blocks pLTF in rats receiving IH or okadaic acid plus SH. Okadaic acid did not alter IH-induced pLTF. In summary, pattern sensitivity in pLTF may reflect differential regulation of okadaic acid-sensitive serine/threonine phosphatases; presumably, these phosphatases are less active during/after IH versus SH. The specific okadaic acid-sensitive phosphatase(s) constraining pLTF and their spatiotemporal dynamics during and/or after IH and SH remain to be determined.

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“…At the end of this pathway, PKG-phosphorylated G-substrate acts as a potent inhibitor of PP1 and PP2A (6)(7)(8). Complex involvement of PPs in cerebellar LTD has been observed in cultured Purkinje cells; myosin/moesin phosphatase (containing PP1 catalytic subunit in its complex) plays a major role at 9-16 days in vitro (DIV) (41), but at 22-35 DIV, PP2A takes over (42). Hence, it is possible that, underlying the age profile of LTD (Fig.…”

Section: Discussionmentioning

confidence: 99%

Dual involvement of G-substrate in motor learning revealed by gene deletion

Endo

Shutoh²,

Dinh³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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In this study, we generated mice lacking the gene for G-substrate, a specific substrate for cGMP-dependent protein kinase uniquely located in cerebellar Purkinje cells, and explored their specific functional deficits. G-substrate-deficient Purkinje cells in slices obtained at postnatal weeks (PWs) 10 -15 maintained electrophysiological properties essentially similar to those from WT littermates. Conjunction of parallel fiber stimulation and depolarizing pulses induced long-term depression (LTD) normally. At younger ages, however, LTD attenuated temporarily at PW6 and recovered thereafter. In parallel with LTD, short-term (1 h) adaptation of optokinetic eye movement response (OKR) temporarily diminished at PW6. Young adult G-substrate knockout mice tested at PW12 exhibited no significant differences from their WT littermates in terms of brain structure, general behavior, locomotor behavior on a rotor rod or treadmill, eyeblink conditioning, dynamic characteristics of OKR, or short-term OKR adaptation. One unique change detected was a modest but significant attenuation in the long-term (5 days) adaptation of OKR. The present results support the concept that LTD is causal to short-term adaptation and reveal the dual functional involvement of G-substrate in neuronal mechanisms of the cerebellum for both short-term and long-term adaptation.cerebellum ͉ long-term depression ͉ optokinetic response ͉ Purkinje cell

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Protein phosphatase 2A inhibition induces cerebellar long-term depression and declustering of synaptic AMPA receptor

Abstract: Phosphorylation of synaptic (RS)-

Cited by 66 publications

References 51 publications

Acute and long-term proteome changes induced by oxidative stress in the developing brain

Acute and long-term proteome changes induced by oxidative stress in the developing brain

Okadaic Acid-Sensitive Protein Phosphatases Constrain Phrenic Long-Term Facilitation after Sustained Hypoxia

Dual involvement of G-substrate in motor learning revealed by gene deletion

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