Functional segregation of voltage-activated calcium channels in motoneurons of the dorsal motor nucleus of the vagus.
Identifieur interne : 000722 ( Main/Exploration ); précédent : 000721; suivant : 000723Functional segregation of voltage-activated calcium channels in motoneurons of the dorsal motor nucleus of the vagus.
Auteurs : Garry Cooper [États-Unis] ; Efrat Lasser-Katz [Israël] ; Alon Simchovitz ; Ronit Sharon [Israël] ; Hermona Soreq ; D James Surmeier [États-Unis] ; Joshua A. Goldberg [Israël]Source :
- Journal of neurophysiology [ 1522-1598 ] ; 2015.
English descriptors
- KwdEn :
- Action Potentials, Animals, Calcium (metabolism), Calcium Channels, L-Type (genetics), Calcium Channels, L-Type (metabolism), Mice, Mice, Inbred C57BL, Motor Neurons (metabolism), Motor Neurons (physiology), Potassium Channels, Calcium-Activated (metabolism), Vagus Nerve (cytology), Vagus Nerve (metabolism), Vagus Nerve (physiology).
- MESH :
- chemical , genetics : Calcium Channels, L-Type.
- chemical , metabolism : Calcium, Calcium Channels, L-Type, Potassium Channels, Calcium-Activated.
- cytology : Vagus Nerve.
- metabolism : Motor Neurons, Vagus Nerve.
- physiology : Motor Neurons, Vagus Nerve.
- Action Potentials, Animals, Mice, Mice, Inbred C57BL.
Abstract
Calcium influx elevates mitochondrial oxidant stress (mOS) in dorsal motor nucleus of the vagus (DMV) neurons that are prone to Lewy body pathologies in presymptomatic Parkinson's disease (PD) patients. In experimental PD models, treatment with isradipine, the dihydropyridine with the highest affinity to Cav1.3 channels, prevents subthreshold calcium influx via Cav1.3 channels into midbrain dopamine neurons and protects them from mOS. In DMV neurons, isradipine is also effective in reducing mOS despite overwhelming evidence that subthreshold calcium influx is negligible compared with spike-triggered influx. To solve this conundrum we combined slice electrophysiology, two-photon laser scanning microscopy, mRNA profiling, and computational modeling. We find that the unusually depolarized subthreshold voltage trajectory of DMV neurons is positioned between the relatively hyperpolarized activation curve of Cav1.3 channels and that of other high-voltage activated (HVA) calcium channels, thus creating a functional segregation between Cav1.3 and HVA calcium channels. The HVA channels flux the bulk of calcium during spikes but can only influence pacemaking through their coupling to calcium-activated potassium currents. In contrast, Cav1.3 currents, which we show to be more than an order-of-magnitude smaller than the HVA calcium currents, are able to introduce sufficient inward current to speed up firing. However, Kv4 channels that are constitutively open in the subthreshold range guarantee slow pacemaking, despite the depolarizing action of Cav1.3 and other pacemaking currents. We propose that the efficacy of isradipine in preventing mOS in DMV neurons arises from its mixed effect on Cav1.3 channels and on HVA Cav1.2 channels.
DOI: 10.1152/jn.00432.2014
PubMed: 26156385
Affiliations:
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In experimental PD models, treatment with isradipine, the dihydropyridine with the highest affinity to Cav1.3 channels, prevents subthreshold calcium influx via Cav1.3 channels into midbrain dopamine neurons and protects them from mOS. In DMV neurons, isradipine is also effective in reducing mOS despite overwhelming evidence that subthreshold calcium influx is negligible compared with spike-triggered influx. To solve this conundrum we combined slice electrophysiology, two-photon laser scanning microscopy, mRNA profiling, and computational modeling. We find that the unusually depolarized subthreshold voltage trajectory of DMV neurons is positioned between the relatively hyperpolarized activation curve of Cav1.3 channels and that of other high-voltage activated (HVA) calcium channels, thus creating a functional segregation between Cav1.3 and HVA calcium channels. The HVA channels flux the bulk of calcium during spikes but can only influence pacemaking through their coupling to calcium-activated potassium currents. In contrast, Cav1.3 currents, which we show to be more than an order-of-magnitude smaller than the HVA calcium currents, are able to introduce sufficient inward current to speed up firing. However, Kv4 channels that are constitutively open in the subthreshold range guarantee slow pacemaking, despite the depolarizing action of Cav1.3 and other pacemaking currents. We propose that the efficacy of isradipine in preventing mOS in DMV neurons arises from its mixed effect on Cav1.3 channels and on HVA Cav1.2 channels.</div></front></TEI><affiliations><list><country><li>Israël</li><li>États-Unis</li></country><region><li>Illinois</li></region></list><tree><noCountry><name sortKey="Simchovitz, Alon" sort="Simchovitz, Alon" uniqKey="Simchovitz A" first="Alon" last="Simchovitz">Alon Simchovitz</name><name sortKey="Soreq, Hermona" sort="Soreq, Hermona" uniqKey="Soreq H" first="Hermona" last="Soreq">Hermona Soreq</name></noCountry><country name="États-Unis"><region name="Illinois"><name sortKey="Cooper, Garry" sort="Cooper, Garry" uniqKey="Cooper G" first="Garry" last="Cooper">Garry Cooper</name></region><name sortKey="Surmeier, D James" sort="Surmeier, D James" uniqKey="Surmeier D" first="D James" last="Surmeier">D James Surmeier</name></country><country name="Israël"><noRegion><name sortKey="Lasser Katz, Efrat" sort="Lasser Katz, Efrat" uniqKey="Lasser Katz E" first="Efrat" last="Lasser-Katz">Efrat Lasser-Katz</name></noRegion><name sortKey="Goldberg, Joshua A" sort="Goldberg, Joshua A" uniqKey="Goldberg J" first="Joshua A" last="Goldberg">Joshua A. Goldberg</name><name sortKey="Sharon, Ronit" sort="Sharon, Ronit" uniqKey="Sharon R" first="Ronit" last="Sharon">Ronit Sharon</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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