Abstract
Inorganic polyphosphate (PolyP) is a negatively charged linear polymer that is found in all living organisms where it has multiple roles. Recently, we showed that inorganic polyphosphate can act as a calcium-dependent gliotransmitter via P2Y1 purinergic receptors of the astrocytes. However, upon exogenous PolyP application, additionally to all astrocytes, 3% of the neurons respond with increased cytosolic calcium and therefore PolyP may be acting as well as a neurotransmitter.Using highly specific fluorescent indicator for inorganic polyphosphate (JC-D8) that we recently developed and a lentiviral delivery of a range of different fluorescent probes to target various types of vesicles, we visualized the release of polyphosphate and study possible interactions between these vesicles and other cellular organelles in primary co-culture of cortical neurons and astrocytes. Co-localisation analysis has shown that PolyP is located mostly in putative ATP-containing vesicles, to a lesser extent in lysosomes and mitochondria and not in the glutamate-containing ones. In TIRF microscopy experiments we have been able to show in-depth release of these vesicles following physiological stimulation. In our hands, release of PolyP out of those vesicles could be stimulated by application of calcium ionophores, protonophores, gpn, PolyP and changes in pH. In live cell imaging experiments in neurons, application of extracellular PolyP can significantly reduce the physiological calcium response to glutamate, by slowing down the Ca2+ efflux in primary neurons, and as well, depending on the length, prevents the delayed calcium deregulation. Furthermore this modulation appears to act via P2Y1 receptors. This study highlights the importance of PolyP in modulating synaptic transmission and perhaps presents as an attractive target for therapy in diseases, where neuronal damage is caused by excitotoxicity.Supported by Leverhulme Trust.
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