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- [Show abstract] [Hide abstract] ABSTRACT: Much excitement surrounded the proposal that a family of endo-lysosomal channels, the two-pore channels (TPCs) were the long sought after targets of the Ca(2+) -mobilising messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). However, the role of TPCs in NAADP signalling may be more complex than originally envisaged. First, NAADP may not bind directly to TPCs but via an accessory protein. Second, two papers recently challenged the notion that TPCs are NAADP-regulated Ca(2+) channels by suggesting that they are highly selective Na(+) channels regulated by the lipid phosphatidylinositol 3,5-bisphosphate and by ATP. This paper aims critically to evaluate the evidence for TPCs as NAADP targets and to discuss how the new findings fit in with what we know about endo-lysosomal Ca(2+) stores.
- [Show abstract] [Hide abstract] ABSTRACT: Almost since the discovery of long-term potentiation (LTP) in the hippocampus, its locus of expression has been debated. Throughout the years, convincing evidence has accumulated to suggest that LTP can be supported either presynaptically, by an increase in transmitter release, or postsynaptically, by an increase in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor number. However, whereas postsynaptic enhancement appears to be consistently obtained across studies following LTP induction, presynaptic enhancement is not as reliably observed. Such discrepancies, along with the failure to convincingly identify a retrograde messenger required for presynaptic change, have led to the general view that LTP is mainly supported postsynaptically, and certainly, research within the field for the past decade has been heavily focused on the postsynaptic locus. Here, we argue that LTP can be expressed at either synaptic locus, but that pre- and postsynaptic forms of LTP are dissociable phenomena mediated by distinct mechanistic processes, which are sensitive to different patterns of neuronal activity. This view of LTP helps to reconcile discrepancies across the literature and may put to rest a decades-long debate.
- [Show abstract] [Hide abstract] ABSTRACT: Niemann-Pick type C (NPC) is a neurodegenerative lysosomal storage disorder caused by defects in the lysosomal proteins NPC1 or NPC2. NPC cells are characterised by reduced lysosomal calcium levels and impaired sphingosine transport from lysosomes. Natural Killer (NK) cells kill virally infected/transformed cells via degranulation of lysosome-related organelles. Their trafficking from lymphoid tissues into the circulation is dependent on sphingosine-1-phosphate (S1P) gradients, sensed by S1P receptor 5 (S1P5). We hypothesised that NK cell function and trafficking could be affected in NPC disease due to the combined effects of the lysosomal calcium defect and sphingosine storage. In an NPC1 mouse model we found the frequency of NK cells was altered and phenocopied S1P5 deficient mice, consistent with defects in S1P levels. NK cells from NPC1 mice also had a defect in cytotoxicty due to a failure in degranulation of cytotoxic granules, which was associated with reduced lysosomal calcium levels. Affected NPC1 patients and NPC1 heterozygote carriers had reduced NK cell numbers in their blood and showed similar phenotypic and developmental changes to those observed in the NPC1 mouse. These findings highlight the effects of lysosomal storage on the peripheral immune system.
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