Cell Membrane Resealing by a Vesicular Mechanism Similar to Neurotransmitter Release

Steinhardt, Richard A.; Bi, Guo-Qiang; Alderton, Janet M.

doi:10.1126/science.7904084

Cited by 477 publications

(513 citation statements)

References 37 publications

(27 reference statements)

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“…This is best demonstrated in red blood cells (40). However, most plasma membrane lesions, particularly if they are large, repair only if intracellular lipids are shuttled to the plasma membrane by an active, energy-dependent, and Ca 2ϩ -regulated process (41)(42)(43). The insertion of lipids into the plasma membrane causes a fall in plasma membrane tension, which in turn promotes "self-sealing" by lateral lipid flow (44,45).…”

Section: Molecular Mechanisms Of Plasma Membrane Repairmentioning

confidence: 99%

Hypercapnic Acidosis Impairs Plasma Membrane Wound Resealing in Ventilator-injured Lungs

Doerr

Gajić

Berríos

et al. 2005

Am J Respir Crit Care Med

118

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The objective of this study was to assess the effects of hypercapnic acidosis on lung cell injury and repair by confocal microscopy in a model of ventilator-induced lung injury. Three groups of normocapnic, hypocapnic, and hypercapnic rat lungs were perfused ex vivo, either during or after injurious ventilation, with a solution containing the membrane-impermeant label propidium iodide. In lungs labeled during injurious ventilation, propidium iodide fluorescence identifies all cells with plasma membrane wounds, both permanent and transient, whereas in lungs labeled after injurious ventilation propidium iodide fluorescence identifies only cells with permanent plasma membrane wounds. Hypercapnia minimized the adverse effects of high-volume ventilation on vascular barrier function, whereas hypocapnia had the opposite effect. Despite CO 2 -dependent differences in lung mechanics and edema the number of injured subpleural cells per alveolus was similar in the three groups (0.48 Ϯ 0.34 versus 0.51 Ϯ 0.19 versus 0.43 Ϯ 0.20 for hypocapnia, normocapnia, and hypercapnia, respectively). However, compared with normocapnia the probability of wound repair was significantly reduced in hypercapnic lungs (63 versus 38%; p Ͻ 0.02). This finding was subsequently confirmed in alveolar epithelial cell scratch models. The potential relevance of these observations for lung inflammation and remodeling after mechanical injury is discussed.Keywords: permissive hypercapnia; plasma membrane wounding and repair; ventilator-induced lung injury So-called lung protective mechanical ventilation strategies emphasize lung recruitment and the avoidance of large tidal volumes. Such strategies are often associated with hypercapnic acidosis. Many experts view "permissive hypercapnia" as a necessary evil of a low tidal ventilation strategy (1). Concern about detrimental effects of acidemia on renal and cardiovascular function have motivated attempts to enhance CO 2 removal by tracheal gas insufflation (2) and have led to unsubstantiated recommendations about the use of bicarbonate buffers in hypercapnic patients (3). More recent data suggest that hypercapnia may actually protect the lung from certain manifestations of ischemiareperfusion, endotoxin, and mechanical ventilation-related injury (4-9). Hypocapnia, in contrast, and correction of acidemia may be harmful (10-12). The specific mechanisms through which hypercapnia influences lung injury and vascular barrier function remain uncertain (13). CO 2 generates H ϩ ions, which react with titratable groups in certain amino acids and/or interacts directly (Received in original form September 3, 2003; accepted in final form January 21, 2005) Supported by grants from the National Institutes of Health (HL-63178), GlaxoSmithKline, and the Brewer Foundation. with free amine groups in proteins to form carbamate residues (14-16). CO 2 -dependent effects on the generation of reactive oxygen species and reactive nitrogen species as well as effects on ion channel conductivity have all been considered (17, 18).V...

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Section: Molecular Mechanisms Of Plasma Membrane Repairmentioning

confidence: 99%

Hypercapnic Acidosis Impairs Plasma Membrane Wound Resealing in Ventilator-injured Lungs

Doerr

Gajić

Berríos

et al. 2005

Am J Respir Crit Care Med

118

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“…Small disruptions on the order of micron-diameter evoke the Ca 2ϩ -dependent exocytosis of vesicles near the wound site, which is essential for successful membrane resealing (2)(3)(4)(5)(6)(7)(8). The recruitment of vesicles to docking sites near the disruption is dependent on the motor proteins, kinesin and myosin, and the activity of Ca 2ϩ /calmodulin-dependent kinase (CaMK) 1 (2,4,9). It has been proposed that wound-induced exocytosis promotes resealing by decreasing membrane tension (10).…”

Section: From the Misaki Marine Biological Station The University Ofmentioning

confidence: 99%

Long-term Potentiation of Wound-induced Exocytosis and Plasma Membrane Repair Is Dependant on cAMP-response Element-mediated Transcription via a Protein Kinase C- and p38 MAPK-dependent Pathway

Togo¹

2004

Journal of Biological Chemistry

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Ca 2؉ -regulated exocytosis is required for rapid resealing of disrupted plasma membranes. It has been previously demonstrated that repeated membrane disruptions reseal more quickly than the initial wound and that this facilitated response requires the transcription factor cAMP-response element-binding protein (CREB). This study examines the signaling pathway between membrane disruption and CREB-dependent gene expression in 3T3 fibroblasts. A reporter gene assay using pCRE-d2EGFP revealed that membrane disruption induced CRE-mediated transcription. Immunofluorescence observations suggested that membrane disruption activated CREB, p38 mitogen-activated protein kinase (p38 MAPK), and MAPK kinase3/6, the kinase responsible for activation of p38 MAPK. CREB phosphorylation upon membrane disruption was inhibited by a specific p38 MAPK inhibitor, SB203580. Both CRE-mediated transcription and long-term potentiation of membrane resealing and wound-induced exocytosis were suppressed when cells were wounded in the presence of either SB203580 or Gö -6976, a specific protein kinase C (PKC) inhibitor. Furthermore, activation of MAPK kinase3/6 was impaired by PKC inhibition during membrane disruption. These results suggest that PKC mediates the stimulation of CREB-dependent gene expression through a p38 MAPK pathway upon membrane disruption.Mechanical stress induces disruptions of plasma membranes in many animal tissues under physiological conditions, and a cell survives these disruptions by rapidly resealing its cell membrane (1). Small disruptions on the order of micron-diameter evoke the Ca 2ϩ -dependent exocytosis of vesicles near the wound site, which is essential for successful membrane resealing (2-8). The recruitment of vesicles to docking sites near the disruption is dependent on the motor proteins, kinesin and myosin, and the activity of Ca 2ϩ /calmodulin-dependent kinase (CaMK) 1 (2, 4, 9). It has been proposed that wound-induced exocytosis promotes resealing by decreasing membrane tension (10).Expression of genes having a cAMP-response element (CRE) can be activated through a variety of signaling cascades that include protein kinase A (PKA), CaMK, and mitogen-activated protein kinase (MAPK) pathways. These pathways are reported to be involved in complex and diverse processes such as learning, memory, synaptic plasticity, development, and stress responses (11)(12)(13)(14). Induction of these signaling pathways activates the transcription factor cAMP-response element binding protein (CREB) by specifically phosphorylating amino acid Ser-133.Wound-induced exocytosis is potentiated following an initial wound so that subsequent cell membrane disruptions reseal more quickly (6, 15). It has also been indicated that the potentiation of membrane resealing and wound-induced exocytosis last at least 24 h after the initial wound and require CREB because a dominant-negative CREB mutant inhibited these processes (15). Furthermore, it has been demonstrated that inhibition of PKA during the initial wound does not affect long-term p...

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“…Membrane resealing is a conserved process by which cells are able to survive mechanical disruption of the plasma membrane (14)(15)(16)(17)(18)(19). Dysferlin-null skeletal and cardiac muscle show enhanced uptake of membrane impermeable dye following laser-induced wounding, suggesting that dysferlin may play a role in membrane resealing (3,20).…”

Section: Introductionmentioning

confidence: 99%

“…Current knowledge of membrane resealing is largely derived from studies in the sea urchin egg and fibroblast model systems, which demonstrated that fusion of intracellular vesicles with the plasma membrane is critical for resealing (15)(16)(17)21). Dysferlin localizes to the plasma membrane and intracellular vesicles in developing myotubes, and interacts with numerous proteins involved in membrane transport, including caveolin-3 (22,23), annexin-4 (5), annexin-6 (24), enlargeosomal marker AHNAK (25) and tubulin (26), but the exact contribution of dysferlincontaining vesicles to resealing following wounding remains elusive, as few studies have examined the behavior of dysferlincontaining vesicles in live cells following cellular wounding.…”

Section: Introductionmentioning

confidence: 99%

Membrane damage-induced vesicle–vesicle fusion of dysferlin-containing vesicles in muscle cells requires microtubules and kinesin

McDade

Michele

2013

Human Molecular Genetics

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Mutations in the dysferlin gene resulting in dysferlin-deficiency lead to limb-girdle muscular dystrophy 2B and Myoshi myopathy in humans. Dysferlin has been proposed as a critical regulator of vesicle-mediated membrane resealing in muscle fibers, and localizes to muscle fiber wounds following sarcolemma damage. Studies in fibroblasts and urchin eggs suggest that trafficking and fusion of intracellular vesicles with the plasma membrane during resealing requires the intracellular cytoskeleton. However, the contribution of dysferlin-containing vesicles to resealing in muscle and the role of the cytoskeleton in regulating dysferlin-containing vesicle biology is unclear. Here, we use live-cell imaging to examine the behavior of dysferlin-containing vesicles following cellular wounding in muscle cells and examine the role of microtubules and kinesin in dysferlin-containing vesicle behavior following wounding. Our data indicate that dysferlin-containing vesicles move along microtubules via the kinesin motor KIF5B in muscle cells. Membrane wounding induces dysferlin-containing vesicle-vesicle fusion and the formation of extremely large cytoplasmic vesicles, and this response depends on both microtubules and functional KIF5B. In non-muscle cell types, lysosomes are critical mediators of membrane resealing, and our data indicate that dysferlincontaining vesicles are capable of fusing with lysosomes following wounding which may contribute to formation of large wound sealing vesicles in muscle cells. Overall, our data provide mechanistic evidence that microtubulebased transport of dysferlin-containing vesicles may be critical for resealing, and highlight a critical role for dysferlin-containing vesicle-vesicle and vesicle-organelle fusion in response to wounding in muscle cells.

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Cell Membrane Resealing by a Vesicular Mechanism Similar to Neurotransmitter Release

Cited by 477 publications

References 37 publications

Hypercapnic Acidosis Impairs Plasma Membrane Wound Resealing in Ventilator-injured Lungs

Hypercapnic Acidosis Impairs Plasma Membrane Wound Resealing in Ventilator-injured Lungs

Long-term Potentiation of Wound-induced Exocytosis and Plasma Membrane Repair Is Dependant on cAMP-response Element-mediated Transcription via a Protein Kinase C- and p38 MAPK-dependent Pathway

Membrane damage-induced vesicle–vesicle fusion of dysferlin-containing vesicles in muscle cells requires microtubules and kinesin

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