PLA2 activity is required for nuclear shrinkage in caspase-independent cell death

Shinzawa, Koei; Tsujimoto, Yoshihide

doi:10.1083/jcb.200306159

Cited by 88 publications

(103 citation statements)

References 45 publications

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“…Such an activation may play a role at least in the prostate, which is not exposed to any essential temperature variations. The link of iPLA 2 to TRPM8 may be important in the establishment of the proapoptotic roles of iPLA 2 (12,24). Indeed, iPLA 2 activation has been implicated in ER stress-induced apoptosis, whereas menthol has been shown to promote apoptosis of LNCaP prostate cancer cells (7).…”

Section: Discussionmentioning

confidence: 99%

Ca2+-independent Phospholipase A2-dependent Gating of TRPM8 by Lysophospholipids

Abeele

Zholos

Bidaux

et al. 2006

Journal of Biological Chemistry

120

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TRPM8 represents an ion channel activated by cold temperatures and cooling agents, such as menthol, that underlies the cold-induced excitation of sensory neurons. Interestingly, the only human tissue outside the peripheral nervous system, in which the expression of TRPM8 transcripts has been detected at high levels, is the prostate, a tissue not exposed to any essential temperature variations. Here we show that the TRPM8 cloned from human prostate and heterologously expressed in HEK-293 cells is regulated by the Ca 2؉ -independent phospholipase A 2 (iPLA 2 ) signaling pathway with its end products, lysophospholipids (LPLs), acting as its endogenous ligands. LPLs induce prominent prolongation of TRPM8 channel openings that are hardly detectable with other stimuli (e.g. cold, menthol, and depolarization) and that account for more than 90% of the total channel open time. Down-regulation of iPLA 2 resulted in a strong inhibition of TRPM8-mediated functional responses and abolished channel activation. The action of LPLs on TRPM8 channels involved either changes in the local lipid bilayer tension or interaction with the critical determinant(s) in the transmembrane channel core. Based on this, we propose a novel concept of TRPM8 regulation with the involvement of iPLA 2 stimulation. This mechanism employs chemical rather than physical (temperature change) signaling and thus may be the main regulator of TRPM8 activation in organs not exposed to any essential temperature variations, as in the prostate gland.Although TRPM8, a member of the transient receptor potential (TRP) 6 channel family, was originally cloned from the prostate (1), recent studies have firmly established its function as a cold/menthol receptor in sensory neurons (2, 3). Thus, an outstanding problem heightened by a significant TRPM8 up-regulation in several tumors (prostate, lung, breasts, skin) concerns the whole spectrum of the physiological and pathophysiological roles of TRPM8 in those tissues devoid of any significant temperature variations. Revealing possible alternative molecular events leading to TRPM8 activation at constant temperature would undoubtedly help to uncover other TRPM8 functions beyond the cold sensation.Recently, a model ascribing TRPM8 activation to cold/menthol-induced shifts in the channel voltage dependence toward physiological membrane potentials has been proposed (4). Although attractive in its explanation of the temperature sensitivity, this model seems to be insufficient to account for TRPM8 activation in those tissues that are not exposed to any essential temperature variations, such as prostate. Moreover, prominent rundown of TRPM8 activity in excised patches (4, 5) raised a possibility that some endogenous ligands might be necessary for channel activation. Phosphatidylinositol 4,5-bisphosphate (PIP 2 ) has recently been found to be such a factor, since it was capable not only of restoring menthol-activated TRPM8 current after its rundown in excised patches but also of activating the current independently of menthol (5, 6...

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Section: Discussionmentioning

confidence: 99%

Ca2+-independent Phospholipase A2-dependent Gating of TRPM8 by Lysophospholipids

Abeele

Zholos

Bidaux

et al. 2006

Journal of Biological Chemistry

120

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“…38 The remodelled membranes generates phagocytic attraction signals to allow correct disposal of the cell remnants created resulting from the apoptotic process. 22,[39][40][41] While not required within apoptotic neurons, complete loss of PLA2G4A and PLA2G2A abolishes inflammation following central nervous system (CNS) injury, and reduces neuronal apoptosis. 19 Studies have shown how PLA2G4A is expressed in adjacent glial cells postinjury, but not within apoptotic neurons.…”

Section: Memory Formation (Long-term Potentiation)mentioning

confidence: 99%

The role of phospholipases A2 in schizophrenia

Law¹,

Cotton²,

Berger

2006

Mol Psychiatry

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A range of neurotransmitter systems have been implicated in the pathogenesis of schizophrenia based on the antidopaminergic activities of antipsychotic medications, and chemicals that can induce psychotic-like symptoms, such as ketamine or PCP. Such neurotransmitter systems often mediate their cellular response via G-protein-coupled release of arachidonic acid (AA) via the activation of phospholipases A2 (PLA2s). The interaction of three PLA2s are important for the regulation of the release of AA -phospholipase A2 Group 2 A, phospholipase A2 Group 4A and phospholipase A2 Group 6A. Gene variations of these three key enzymes have been associated with schizophrenia with conflicting results. Preclinical data suggest that the activity of these three enzymes are associated with monoaminergic neurotransmission, and may contribute to the differential efficacy of antipsychotic medications, as well as other biological changes thought to underlie schizophrenia, such as altered neurodevelopment and synaptic remodelling. We review the evidence and discuss the potential roles of these three key enzymes for schizophrenia with particular emphasis on published association studies.

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“…Thus the role of acinus in apoptotic chromatin condensation is uncertain. More recently, phospholipase A2 (PLA2) was reported to induce nuclear shrinkage without fragmentation during caspase-independent cell death induced by hypoxia [9].…”

Section: Introductionmentioning

confidence: 99%

Three distinct stages of apoptotic nuclear condensation revealed by time-lapse imaging, biochemical and electron microscopy analysis of cell-free apoptosis

Toné¹,

Sugimoto²,

Tanda³

et al. 2007

Experimental Cell Research

181

129

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During apoptotic execution, chromatin undergoes a phase change from a heterogeneous, genetically active network to an inert highly condensed form that is fragmented and packaged into apoptotic bodies. We have previously used a cell-free system to examine the roles of caspases or other proteases in apoptotic chromatin condensation and nuclear disassembly. But so far, the role of DNase activity or ATP hydrolysis in this system has not yet been elucidated. Here, in order to better define the stages of nuclear disassembly in apoptosis, we have characterized the apoptotic condensation using a cellfree system and time-lapse imaging. We demonstrated that the population of nuclei undergoing apoptosis in vitro appears to follow a reproducible program of nuclear condensation, suggesting the existence of an ordered biochemical pathway. This enabled us to define three stages of apoptotic chromatin condensation: Stage 1 ring condensation; Stage 2 necklace condensation; and Stage 3 nuclear collapse/disassembly. Electron microscopy revealed that neither chromatin nor detectible subnuclear structures were present inside the stage 1 ring-condensed structures. DNase activity was not essential for stage 1 ring condensation, which could occur in apoptotic extracts depleted of all detectible DNase activity. However, DNase(s) were required for stage 2 necklace condensation. Finally, we demonstrated that hydrolysable ATP is required for stage 3 nuclear collapse/disassembly. This requirement for ATP hydrolysis further distinguished stage 2 from stage 3. Together, these experiments provide the first steps towards a systematic biochemical characterization of chromatin condensation during apoptosis.

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PLA2 activity is required for nuclear shrinkage in caspase-independent cell death

Cited by 88 publications

References 45 publications

Ca2+-independent Phospholipase A2-dependent Gating of TRPM8 by Lysophospholipids

Ca2+-independent Phospholipase A2-dependent Gating of TRPM8 by Lysophospholipids

The role of phospholipases A2 in schizophrenia

Three distinct stages of apoptotic nuclear condensation revealed by time-lapse imaging, biochemical and electron microscopy analysis of cell-free apoptosis

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