title: Functional segregation of voltage-activated calcium channels in motoneurons of the dorsal motor nucleus of the vagus.
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.
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois;
authors.forename: Garry
authors.initials: G
authors.lastname: Cooper
authors.affiliation: Department of Medical Neurobiology, Institute of Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel;
authors.forename: Efrat
authors.initials: E
authors.lastname: Lasser-Katz
authors.affiliation: The Edmond and Lily Safra Center for Brain Sciences and The Life Sciences Institute, The Hebrew University of Jerusalem, Jerusalem, Israel; and.
authors.forename: Alon
authors.initials: A
authors.lastname: Simchovitz
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Sharon
authors.affiliation: The Edmond and Lily Safra Center for Brain Sciences and The Life Sciences Institute, The Hebrew University of Jerusalem, Jerusalem, Israel; and.
authors.forename: Hermona
authors.initials: H
authors.lastname: Soreq
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois;
authors.forename: D James
authors.initials: DJ
authors.lastname: Surmeier
authors.affiliation: Department of Medical Neurobiology, Institute of Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel; joshg@ekmd.huji.ac.il.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Goldberg
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000378:metabolism* / Q000502:physiology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D014630:Vagus Nerve / Q000166:cytology / Q000378:metabolism* / Q000502:physiology
chemical_list: C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type; D024681:Potassium Channels, Calcium-Activated; D002118:Calcium
keywords: Cav1.2; Cav1.3; Cav2; Hodgkin class I excitability; Kv4; Lewy body neurite pathology; NALCN; Parkinson's disease; Traub model; calcium dynamics; calcium imaging; isradipine; lingering; mitochondrial oxidative stress; modeling; mouse; two-photon laser scanning microscopy; vagal motoneurons; window current