In dopaminergic (DA) substantia nigra (SN) neurons Cav2.3 R-type Ca2+-currents contribute to somatodendritic Ca2+-oscillations. This activity may contribute to the selective degeneration of these neurons in Parkinson's disease (PD) since Cav2.3-knockout is neuroprotective in a PD mouse model. Here we show that in tsA-201-cells the membrane-anchored β2-splice variants β2a and β2e are required to stabilize Cav2.3 gating properties allowing sustained Cav2.3 availability during simulated pacemaking and enhanced Ca2+-currents during bursts. We confirmed the expression of β2a- and β2e-subunit transcripts in the mouse SN and in identified SN DA neurons. Patch-clamp recordings of mouse DA midbrain neurons in culture and SN DA neurons in brain slices revealed SNX-482-sensitive R-type Ca2+-currents with voltage-dependent gating properties that suggest modulation by β2a- and/or β2e-subunits. Thus, β-subunit alternative splicing may prevent a fraction of Cav2.3 channels from inactivation in continuously active, highly vulnerable SN DA neurons, thereby also supporting Ca2+ signals contributing to the (patho)physiological role of Cav2.3 channels in PD.
All data generated or analyzed during this study are included in the manuscript and supporting files. Raw data have been provided for mean population data shown in Figures and Tables.
RNASeq of DA neurons from SNpc and VTA. Dataset posted on 04.03.2015, 16:01 by William Shindoi.org/10.6084/m9.figshare.926519.v1.
RNA Sequencing Identifies Robust Markers of Vulnerable and Resistant Human Midbrain Dopamine Neurons and Their Expression in Parkinson's DiseaseNCBI Gene Expression Omnibus, GSE114918.
- Jörg Striessnig
- Nadine Jasmin Ortner
- Emilio Carbone
- Emilio Carbone
- Nadine Jasmin Ortner
- Birgit Liss
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All animal experiments and procedures were performed in strict accordance with the European Community's Council Directive 2010/63/UE and approved by the Italian Ministry of Health and the Local Organism responsible for animal welfare at the University of Torino (authorization DGSAF 0011710-P-26/07/2017) and the local authorities at the University of Ulm (Regierungspräsidium Tübingen, Ref: 35/9185.81-3; Reg. Nr. o.147) and University of Cologne (LANUV NRW, Recklinghausen, Germany (84-02.05.20.12.254).
- Henry M Colecraft, Columbia University, United States
- Preprint posted: February 10, 2021 (view preprint)
- Received: February 11, 2021
- Accepted: July 4, 2022
- Accepted Manuscript published: July 6, 2022 (version 1)
- Accepted Manuscript updated: July 8, 2022 (version 2)
- Version of Record published: July 22, 2022 (version 3)
- Version of Record updated: July 27, 2022 (version 4)
© 2022, Siller et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
The Hydra nervous system is the paradigm of a ‘simple nerve net’. Nerve cells in Hydra, as in many cnidarian polyps, are organized in a nerve net extending throughout the body column. This nerve net is required for control of spontaneous behavior: elimination of nerve cells leads to polyps that do not move and are incapable of capturing and ingesting prey (Campbell, 1976). We have re-examined the structure of the Hydra nerve net by immunostaining fixed polyps with a novel antibody that stains all nerve cells in Hydra. Confocal imaging shows that there are two distinct nerve nets, one in the ectoderm and one in the endoderm, with the unexpected absence of nerve cells in the endoderm of the tentacles. The nerve nets in the ectoderm and endoderm do not contact each other. High-resolution TEM (transmission electron microscopy) and serial block face SEM (scanning electron microscopy) show that the nerve nets consist of bundles of parallel overlapping neurites. Results from transgenic lines show that neurite bundles include different neural circuits and hence that neurites in bundles require circuit-specific recognition. Nerve cell-specific innexins indicate that gap junctions can provide this specificity. The occurrence of bundles of neurites supports a model for continuous growth and differentiation of the nerve net by lateral addition of new nerve cells to the existing net. This model was confirmed by tracking newly differentiated nerve cells.
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