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

Stephanie C. Stotz, Lucas Om Scott, Christopher Drummond-Main, Yosef Avchalumov, Fernando Girotto, Jörn Davidsen, Maria R. Gómez-Gárcia, Jong M. Rho, Evgeny Pavlov, Michael A. Colicos

Research output: Contribution to journalArticle

Abstract

Background: Inorganic 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. Results: Using 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. Conclusions: We 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.

Original languageEnglish (US)
Article number42
JournalMolecular Brain
Volume7
Issue number1
DOIs
StatePublished - May 31 2014

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Polyphosphates
Neurons
Astrocytes
Calcium
Membranes
Potassium Chloride
Synaptosomes
Spinal Ganglia
Blood Coagulation
Patch-Clamp Techniques
Ion Channels
Neuroglia
Membrane Potentials
Action Potentials
Extracellular Matrix
Neurotransmitter Agents
Blood Platelets
Cell Culture Techniques

Keywords

  • Inflammation
  • Neuroactive compounds
  • Neuronal activity
  • Pain
  • Platelets
  • Polyphosphate
  • Synaptic transmission
  • Synaptic vesicles
  • Voltage gated channels

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Molecular Biology

Cite this

Stotz, S. C., Scott, L. O., Drummond-Main, C., Avchalumov, Y., Girotto, F., Davidsen, J., ... Colicos, M. A. (2014). Inorganic polyphosphate regulates neuronal excitability through modulation of voltage-gated channels. Molecular Brain, 7(1), [42]. https://doi.org/10.1186/1756-6606-7-42

Inorganic polyphosphate regulates neuronal excitability through modulation of voltage-gated channels. / Stotz, Stephanie C.; Scott, Lucas Om; Drummond-Main, Christopher; Avchalumov, Yosef; Girotto, Fernando; Davidsen, Jörn; Gómez-Gárcia, Maria R.; Rho, Jong M.; Pavlov, Evgeny; Colicos, Michael A.

In: Molecular Brain, Vol. 7, No. 1, 42, 31.05.2014.

Research output: Contribution to journalArticle

Stotz, SC, Scott, LO, Drummond-Main, C, Avchalumov, Y, Girotto, F, Davidsen, J, Gómez-Gárcia, MR, Rho, JM, Pavlov, E & Colicos, MA 2014, 'Inorganic polyphosphate regulates neuronal excitability through modulation of voltage-gated channels', Molecular Brain, vol. 7, no. 1, 42. https://doi.org/10.1186/1756-6606-7-42
Stotz SC, Scott LO, Drummond-Main C, Avchalumov Y, Girotto F, Davidsen J et al. Inorganic polyphosphate regulates neuronal excitability through modulation of voltage-gated channels. Molecular Brain. 2014 May 31;7(1). 42. https://doi.org/10.1186/1756-6606-7-42
Stotz, Stephanie C. ; Scott, Lucas Om ; Drummond-Main, Christopher ; Avchalumov, Yosef ; Girotto, Fernando ; Davidsen, Jörn ; Gómez-Gárcia, Maria R. ; Rho, Jong M. ; Pavlov, Evgeny ; Colicos, Michael A. / Inorganic polyphosphate regulates neuronal excitability through modulation of voltage-gated channels. In: Molecular Brain. 2014 ; Vol. 7, No. 1.
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AU - Davidsen, Jörn

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