The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors
Peripheral nociceptive neurons encode and convey injury-inducing stimuli toward the central nervous system. In normal conditions, tight control of nociceptive resting potential prevents their spontaneous activation. However, in many pathological conditions the control of membrane potential is disrup...
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Frontiers Media S.A.
2017-06-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00181/full |
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| author | Omer Barkai Omer Barkai Robert H. Goldstein Robert H. Goldstein Yaki Caspi Yaki Caspi Ben Katz Ben Katz Shaya Lev Shaya Lev Alexander M. Binshtok Alexander M. Binshtok |
| author_facet | Omer Barkai Omer Barkai Robert H. Goldstein Robert H. Goldstein Yaki Caspi Yaki Caspi Ben Katz Ben Katz Shaya Lev Shaya Lev Alexander M. Binshtok Alexander M. Binshtok |
| author_sort | Omer Barkai |
| collection | DOAJ |
| description | Peripheral nociceptive neurons encode and convey injury-inducing stimuli toward the central nervous system. In normal conditions, tight control of nociceptive resting potential prevents their spontaneous activation. However, in many pathological conditions the control of membrane potential is disrupted, leading to ectopic, stimulus-unrelated firing of nociceptive neurons, which is correlated to spontaneous pain. We have investigated the role of KV7/M channels in stabilizing membrane potential and impeding spontaneous firing of nociceptive neurons. These channels generate low voltage-activating, noninactivating M-type K+ currents (M-current, IM), which control neuronal excitability. Using perforated-patch recordings from cultured, rat nociceptor-like dorsal root ganglion neurons, we show that inhibition of M-current leads to depolarization of nociceptive neurons and generation of repetitive firing. To assess to what extent the M-current, acting at the nociceptive terminals, is able to stabilize terminals' membrane potential, thus preventing their ectopic activation, in normal and pathological conditions, we built a multi-compartment computational model of a pseudo-unipolar unmyelinated nociceptive neuron with a realistic terminal tree. The modeled terminal tree was based on the in vivo structure of nociceptive peripheral terminal, which we assessed by in vivo multiphoton imaging of GFP-expressing nociceptive neuronal terminals innervating mice hind paw. By modifying the conductance of the KV7/M channels at the modeled terminal tree (terminal gKV7/M) we have found that 40% of the terminal gKV7/M conductance is sufficient to prevent spontaneous firing, while ~75% of terminal gKV7/M is sufficient to inhibit stimulus induced activation of nociceptive neurons. Moreover, we showed that terminal M-current reduces susceptibility of nociceptive neurons to a small fluctuations of membrane potentials. Furthermore, we simulated how the interaction between terminal persistent sodium current and M-current affects the excitability of the neurons. We demonstrated that terminal M-current in nociceptive neurons impeded spontaneous firing even when terminal Na(V)1.9 channels conductance was substantially increased. On the other hand, when terminal gKV7/M was decreased, nociceptive neurons fire spontaneously after slight increase in terminal Na(V)1.9 conductance. Our results emphasize the pivotal role of M-current in stabilizing membrane potential and hereby in controlling nociceptive spontaneous firing, in normal and pathological conditions. |
| first_indexed | 2024-12-13T08:28:08Z |
| format | Article |
| id | doaj.art-c98e7d3618be4e05876e094fc9108922 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-13T08:28:08Z |
| publishDate | 2017-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-c98e7d3618be4e05876e094fc91089222022-12-21T23:53:50ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992017-06-011010.3389/fnmol.2017.00181275740The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in NociceptorsOmer Barkai0Omer Barkai1Robert H. Goldstein2Robert H. Goldstein3Yaki Caspi4Yaki Caspi5Ben Katz6Ben Katz7Shaya Lev8Shaya Lev9Alexander M. Binshtok10Alexander M. Binshtok11Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Hadassah School of Medicine, The Hebrew University-Hadassah School of MedicineJerusalem, IsraelThe Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of JerusalemJerusalem, IsraelDepartment of Medical Neurobiology, Institute for Medical Research Israel-Canada, Hadassah School of Medicine, The Hebrew University-Hadassah School of MedicineJerusalem, IsraelThe Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of JerusalemJerusalem, IsraelDepartment of Medical Neurobiology, Institute for Medical Research Israel-Canada, Hadassah School of Medicine, The Hebrew University-Hadassah School of MedicineJerusalem, IsraelThe Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of JerusalemJerusalem, IsraelDepartment of Medical Neurobiology, Institute for Medical Research Israel-Canada, Hadassah School of Medicine, The Hebrew University-Hadassah School of MedicineJerusalem, IsraelThe Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of JerusalemJerusalem, IsraelDepartment of Medical Neurobiology, Institute for Medical Research Israel-Canada, Hadassah School of Medicine, The Hebrew University-Hadassah School of MedicineJerusalem, IsraelThe Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of JerusalemJerusalem, IsraelDepartment of Medical Neurobiology, Institute for Medical Research Israel-Canada, Hadassah School of Medicine, The Hebrew University-Hadassah School of MedicineJerusalem, IsraelThe Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of JerusalemJerusalem, IsraelPeripheral nociceptive neurons encode and convey injury-inducing stimuli toward the central nervous system. In normal conditions, tight control of nociceptive resting potential prevents their spontaneous activation. However, in many pathological conditions the control of membrane potential is disrupted, leading to ectopic, stimulus-unrelated firing of nociceptive neurons, which is correlated to spontaneous pain. We have investigated the role of KV7/M channels in stabilizing membrane potential and impeding spontaneous firing of nociceptive neurons. These channels generate low voltage-activating, noninactivating M-type K+ currents (M-current, IM), which control neuronal excitability. Using perforated-patch recordings from cultured, rat nociceptor-like dorsal root ganglion neurons, we show that inhibition of M-current leads to depolarization of nociceptive neurons and generation of repetitive firing. To assess to what extent the M-current, acting at the nociceptive terminals, is able to stabilize terminals' membrane potential, thus preventing their ectopic activation, in normal and pathological conditions, we built a multi-compartment computational model of a pseudo-unipolar unmyelinated nociceptive neuron with a realistic terminal tree. The modeled terminal tree was based on the in vivo structure of nociceptive peripheral terminal, which we assessed by in vivo multiphoton imaging of GFP-expressing nociceptive neuronal terminals innervating mice hind paw. By modifying the conductance of the KV7/M channels at the modeled terminal tree (terminal gKV7/M) we have found that 40% of the terminal gKV7/M conductance is sufficient to prevent spontaneous firing, while ~75% of terminal gKV7/M is sufficient to inhibit stimulus induced activation of nociceptive neurons. Moreover, we showed that terminal M-current reduces susceptibility of nociceptive neurons to a small fluctuations of membrane potentials. Furthermore, we simulated how the interaction between terminal persistent sodium current and M-current affects the excitability of the neurons. We demonstrated that terminal M-current in nociceptive neurons impeded spontaneous firing even when terminal Na(V)1.9 channels conductance was substantially increased. On the other hand, when terminal gKV7/M was decreased, nociceptive neurons fire spontaneously after slight increase in terminal Na(V)1.9 conductance. Our results emphasize the pivotal role of M-current in stabilizing membrane potential and hereby in controlling nociceptive spontaneous firing, in normal and pathological conditions.http://journal.frontiersin.org/article/10.3389/fnmol.2017.00181/fullM-currentspontaneous firingectopic activitynociceptorsnociceptive terminals |
| spellingShingle | Omer Barkai Omer Barkai Robert H. Goldstein Robert H. Goldstein Yaki Caspi Yaki Caspi Ben Katz Ben Katz Shaya Lev Shaya Lev Alexander M. Binshtok Alexander M. Binshtok The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors Frontiers in Molecular Neuroscience M-current spontaneous firing ectopic activity nociceptors nociceptive terminals |
| title | The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors |
| title_full | The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors |
| title_fullStr | The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors |
| title_full_unstemmed | The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors |
| title_short | The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors |
| title_sort | role of kv7 m potassium channels in controlling ectopic firing in nociceptors |
| topic | M-current spontaneous firing ectopic activity nociceptors nociceptive terminals |
| url | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00181/full |
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