Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels
Increasing extracellular [Ca2+] ([Ca2+]o) strongly decreases intrinsic excitability in neurons but the mechanism is unclear. By one hypothesis, [Ca2+]o screens surface charge, reducing voltage-gated sodium channel (VGSC) activation and by another [Ca2+]o activates Calcium-sensing receptor (CaSR) clo...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/67914 |
| _version_ | 1811180332471287808 |
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| author | Briana J Martiszus Timur Tsintsadze Wenhan Chang Stephen M Smith |
| author_facet | Briana J Martiszus Timur Tsintsadze Wenhan Chang Stephen M Smith |
| author_sort | Briana J Martiszus |
| collection | DOAJ |
| description | Increasing extracellular [Ca2+] ([Ca2+]o) strongly decreases intrinsic excitability in neurons but the mechanism is unclear. By one hypothesis, [Ca2+]o screens surface charge, reducing voltage-gated sodium channel (VGSC) activation and by another [Ca2+]o activates Calcium-sensing receptor (CaSR) closing the sodium-leak channel (NALCN). Here we report that neocortical neurons from CaSR-deficient (Casr-/-) mice had more negative resting potentials and did not fire spontaneously in reduced divalent-containing solution (T0.2) in contrast with wild-type (WT). However, after setting membrane potential to −70 mV, T0.2 application similarly depolarized and increased action potential firing in Casr-/- and WT neurons. Enhanced activation of VGSCs was the dominant contributor to the depolarization and increase in excitability by T0.2 and occurred due to hyperpolarizing shifts in VGSC window currents. CaSR deletion depolarized VGSC window currents but did not affect NALCN activation. Regulation of VGSC gating by external divalents is the key mechanism mediating divalent-dependent changes in neocortical neuron excitability. |
| first_indexed | 2024-04-11T09:00:14Z |
| format | Article |
| id | doaj.art-14c7751dfe664041ab8b0e34b93d6dfa |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:00:14Z |
| publishDate | 2021-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-14c7751dfe664041ab8b0e34b93d6dfa2022-12-22T04:32:47ZengeLife Sciences Publications LtdeLife2050-084X2021-05-011010.7554/eLife.67914Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channelsBriana J Martiszus0Timur Tsintsadze1Wenhan Chang2Stephen M Smith3https://orcid.org/0000-0002-0331-7615Section of Pulmonary & Critical Care Medicine, VA Portland Health Care System, Portland, United States; Department of Medicine, Division of Pulmonary & Critical Care Medicine, Oregon Health & Science University, Portland, United StatesSection of Pulmonary & Critical Care Medicine, VA Portland Health Care System, Portland, United States; Department of Medicine, Division of Pulmonary & Critical Care Medicine, Oregon Health & Science University, Portland, United StatesEndocrine Research Unit, Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, United StatesSection of Pulmonary & Critical Care Medicine, VA Portland Health Care System, Portland, United States; Department of Medicine, Division of Pulmonary & Critical Care Medicine, Oregon Health & Science University, Portland, United StatesIncreasing extracellular [Ca2+] ([Ca2+]o) strongly decreases intrinsic excitability in neurons but the mechanism is unclear. By one hypothesis, [Ca2+]o screens surface charge, reducing voltage-gated sodium channel (VGSC) activation and by another [Ca2+]o activates Calcium-sensing receptor (CaSR) closing the sodium-leak channel (NALCN). Here we report that neocortical neurons from CaSR-deficient (Casr-/-) mice had more negative resting potentials and did not fire spontaneously in reduced divalent-containing solution (T0.2) in contrast with wild-type (WT). However, after setting membrane potential to −70 mV, T0.2 application similarly depolarized and increased action potential firing in Casr-/- and WT neurons. Enhanced activation of VGSCs was the dominant contributor to the depolarization and increase in excitability by T0.2 and occurred due to hyperpolarizing shifts in VGSC window currents. CaSR deletion depolarized VGSC window currents but did not affect NALCN activation. Regulation of VGSC gating by external divalents is the key mechanism mediating divalent-dependent changes in neocortical neuron excitability.https://elifesciences.org/articles/67914calciumsurface chargeVGSCNALCNCaSRexcitability |
| spellingShingle | Briana J Martiszus Timur Tsintsadze Wenhan Chang Stephen M Smith Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels eLife calcium surface charge VGSC NALCN CaSR excitability |
| title | Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels |
| title_full | Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels |
| title_fullStr | Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels |
| title_full_unstemmed | Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels |
| title_short | Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels |
| title_sort | enhanced excitability of cortical neurons in low divalent solutions is primarily mediated by altered voltage dependence of voltage gated sodium channels |
| topic | calcium surface charge VGSC NALCN CaSR excitability |
| url | https://elifesciences.org/articles/67914 |
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