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 language | English (US) |
|---|---|
| Article number | 42 |
| Journal | Molecular Brain |
| Volume | 7 |
| Issue number | 1 |
| DOIs | |
| State | Published - May 31 2014 |
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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
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 journal › Article
}
TY - JOUR
T1 - Inorganic polyphosphate regulates neuronal excitability through modulation of voltage-gated channels
AU - Stotz, Stephanie C.
AU - Scott, Lucas Om
AU - Drummond-Main, Christopher
AU - Avchalumov, Yosef
AU - Girotto, Fernando
AU - Davidsen, Jörn
AU - Gómez-Gárcia, Maria R.
AU - Rho, Jong M.
AU - Pavlov, Evgeny
AU - Colicos, Michael A.
PY - 2014/5/31
Y1 - 2014/5/31
N2 - 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.
AB - 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.
KW - Inflammation
KW - Neuroactive compounds
KW - Neuronal activity
KW - Pain
KW - Platelets
KW - Polyphosphate
KW - Synaptic transmission
KW - Synaptic vesicles
KW - Voltage gated channels
UR - http://www.scopus.com/inward/record.url?scp=84902833632&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84902833632&partnerID=8YFLogxK
U2 - 10.1186/1756-6606-7-42
DO - 10.1186/1756-6606-7-42
M3 - Article
C2 - 24886461
AN - SCOPUS:84902833632
VL - 7
JO - Molecular Brain
JF - Molecular Brain
SN - 1756-6606
IS - 1
M1 - 42
ER -