Inorganic polyphosphate regulates neuronal excitability through modulation of voltage-gated channels

Abstract

BackgroundInorganic polyphosphate (polyP) is a highly charged polyanion capable of interacting with a number of molecular targets. This signaling molecule is released into the extracellular matrix by central astrocytes and by peripheral platelets during inflammation. While the release of polyP is associated with both induction of blood coagulation and astrocyte extracellular signaling, the role of secreted polyP in regulation of neuronal activity remains undefined. Here we test the hypothesis that polyP is an important participant in neuronal signaling. Specifically, we investigate the ability of neurons to release polyP and to induce neuronal firing, and clarify the underlying molecular mechanisms of this process by studying the action of polyP on voltage gated channels.ResultsUsing patch clamp techniques, and primary hippocampal and dorsal root ganglion cell cultures, we demonstrate that polyP directly influences neuronal activity, inducing action potential generation in both PNS and CNS neurons. Mechanistically, this is accomplished by shifting the voltage sensitivity of NaV channel activation toward the neuronal resting membrane potential, the block KV channels, and the activation of CaV channels. Next, using calcium imaging we found that polyP stimulates an increase in neuronal network activity and induces calcium influx in glial cells. Using in situ DAPI localization and live imaging, we demonstrate that polyP is naturally present in synaptic regions and is released from the neurons upon depolarization. Finally, using a biochemical assay we demonstrate that polyP is present in synaptosomes and can be released upon their membrane depolarization by the addition of potassium chloride.ConclusionsWe conclude that polyP release leads to increased excitability of the neuronal membrane through the modulation of voltage gated ion channels. Together, our data establishes that polyP could function as excitatory neuromodulator in both the PNS and CNS.

Physiological roles of the mitochondrial permeability transition pore

“…In contrast, PT is inhibited by ATP/ADP and Mg 2+ (Kowaltowski et al, 1998; Crompton, 1999). Recent reports have also confirmed increased propensity toward PT caused by the presence of polyphosphates, chains of 10s to 100 s of repeating phosphates linked by ATP-like high energy bonds (Abramov et al, 2007; Seidlmayer et al, 2012; Holmstrom et al, 2013; Stotz et al, 2014). The actions of Ca 2+ may also require polyhydroxybutyrate (PHB), which enters mitochondria and enhances the ability of Ca 2+ to induce PT (Elustondo et al, 2013).…”

Inorganic polyphosphates enhances nucleus pulposus tissue formation in vitro

“…36 Interestingly a differential response by mammalian cell types to different chain lengths of polyP has been observed. For example polyP between 25 and 75 chain lengths enhance mineralization by bone cells, 22,37 whereas, chondrocytes respond anabolically to polyP with a chain length of 45, 25 neurons to polyP with a chain length 60, 20,38 and platelets to 60-100 residues. 39 One possible explanation for chain length specificity is polyP's role in forming ion channels.…”

Cell death disguised: The mitochondrial permeability transition pore as the c-subunit of the F1FO ATP synthase

“…In contrast, it is inhibited by ATP/ADP and Mg 2+ [40,57]. Recent reports have also confirmed increased activity of PT by polyphosphates, chains of 10s to 100s of repeating phosphates linked by ATP-like high energy bonds [58–61]. The actions of Ca 2+ may also require polyhydroxybutyrate (PHB), which enters mitochondria and enhances the ability of Ca 2+ to induce PT [62].…”