title: Inorganic polyphosphate regulates neuronal excitability through modulation of voltage-gated channels.
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.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Stotz
authors.forename: Lucas Om
authors.initials: LO
authors.lastname: Scott
authors.forename: Christopher
authors.initials: C
authors.lastname: Drummond-Main
authors.forename: Yosef
authors.initials: Y
authors.lastname: Avchalumov
authors.forename: Fernando
authors.initials: F
authors.lastname: Girotto
authors.forename: Jörn
authors.initials: J
authors.lastname: Davidsen
authors.forename: Maria R
authors.initials: MR
authors.lastname: Gómez-Gárcia
authors.forename: Jong M
authors.initials: JM
authors.lastname: Rho
authors.forename: Evgeny V
authors.initials: EV
authors.lastname: Pavlov
authors.affiliation: Department of Physiology & Pharmacology and the Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada. mcolicos@ucalgary.ca.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Colicos
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007211:Indoles / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011122:Polyphosphates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D007211:Indoles; D011122:Polyphosphates; D061566:Voltage-Gated Sodium Channels; C007293:DAPI