Alteration of the nuclear pore complex in Ca(2+)-mediated cell death.
Cell death requires coordinated intracellular signalling before disassembly of cell architecture by degradative enzymes. Although the death signalling cascades that involve the mitochondria, the ER and the plasma membrane have been extensively characterized, only a handful of studies have examined the functional and structural alterations of the nuclear pore complex (NPC) during neuronal death. Here, we show that during excitotoxic neuronal degeneration calpains redistributed across the nuclear envelope and mediated the degradation of NPC components causing altered permeability of the nuclear membrane. In primary dissociated neurons, simultaneous recording of cytosolic [Ca(2+)] and localization of fluorescent proteins showed that the onset of Ca(2+) overload signalled a progressive increase in the diffusion of small reporter molecules across the nuclear envelope. Later, calpain-mediated changes in nuclear pore permeability allowed accumulation of large proteins in the nucleus. Further, in a model of excitotoxic neuronal degeneration in Caenorhabditis elegans, we found similar nuclear changes and redistribution of fluorescent probes across the nuclear membrane in dying neurons. Our findings strongly suggest that increased leakiness of the nuclear barrier affects nucleocytoplasmic transport, alters the localization of proteins across the nuclear envelope and it is likely to be involved in Ca(2+)-dependent cell death, including ischemic neuronal demise.
Bano
D
D
MRC Toxicology Unit, Hodgkin Building, University of Leicester, Leicester LE1 9HN, UK. db81@le.ac.uk
Dinsdale
D
D
Cabrera-Socorro
A
A
Maida
S
S
Lambacher
N
N
McColl
B
B
Ferrando-May
E
E
Hengartner
M O
MO
Nicotera
P
P
D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000494:pharmacology; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D022022:Nuclear Pore / Q000502:physiology*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism; D015398:Signal Transduction
D029742:Caenorhabditis elegans Proteins; C454142:DEG-3 protein, C elegans; D028861:Nuclear Pore Complex Proteins; D011978:Receptors, Nicotinic; D018698:Glutamic Acid; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); D002154:Calpain; D002118:Calcium