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, 139 Suppl 1 (Suppl Suppl 1), 156-178

Converging Roles of Ion Channels, Calcium, Metabolic Stress, and Activity Pattern of Substantia Nigra Dopaminergic Neurons in Health and Parkinson's Disease


Converging Roles of Ion Channels, Calcium, Metabolic Stress, and Activity Pattern of Substantia Nigra Dopaminergic Neurons in Health and Parkinson's Disease

Johanna Duda et al. J Neurochem.


Dopamine-releasing neurons within the Substantia nigra (SN DA) are particularly vulnerable to degeneration compared to other dopaminergic neurons. The age-dependent, progressive loss of these neurons is a pathological hallmark of Parkinson's disease (PD), as the resulting loss of striatal dopamine causes its major movement-related symptoms. SN DA neurons release dopamine from their axonal terminals within the dorsal striatum, and also from their cell bodies and dendrites within the midbrain in a calcium- and activity-dependent manner. Their intrinsically generated and metabolically challenging activity is created and modulated by the orchestrated function of different ion channels and dopamine D2-autoreceptors. Here, we review increasing evidence that the mechanisms that control activity patterns and calcium homeostasis of SN DA neurons are not only crucial for their dopamine release within a physiological range but also modulate their mitochondrial and lysosomal activity, their metabolic stress levels, and their vulnerability to degeneration in PD. Indeed, impaired calcium homeostasis, lysosomal and mitochondrial dysfunction, and metabolic stress in SN DA neurons represent central converging trigger factors for idiopathic and familial PD. We summarize double-edged roles of ion channels, activity patterns, calcium homeostasis, and related feedback/feed-forward signaling mechanisms in SN DA neurons for maintaining and modulating their physiological function, but also for contributing to their vulnerability in PD-paradigms. We focus on the emerging roles of maintained neuronal activity and calcium homeostasis within a physiological bandwidth, and its modulation by PD-triggers, as well as on bidirectional functions of voltage-gated L-type calcium channels and metabolically gated ATP-sensitive potassium (K-ATP) channels, and their probable interplay in health and PD. We propose that SN DA neurons possess several feedback and feed-forward mechanisms to protect and adapt their activity-pattern and calcium-homeostasis within a physiological bandwidth, and that PD-trigger factors can narrow this bandwidth. We summarize roles of ion channels in this view, and findings documenting that both, reduced as well as elevated activity and associated calcium-levels can trigger SN DA degeneration. This article is part of a special issue on Parkinson disease.

Keywords: A-type Kv4.3/KChip3 potassium channels; Cav1.3 L-type/Cav3.1 T-type calcium channels; D2-autoreceptor-coupled GIRK2 channels; Kir6.2/SUR1 potassium channels; ambroxol; neuronal calcium sensor NCS-1.


Figure 1
Figure 1
Converging pathways of ion channel activities, Ca2+ homeostasis and metabolic stress in Substantia nigra dopaminergic neurons in health and Parkinson's disease. Upper: Whole‐cell current clamp recording of a SN DA neuron (shown left as a projection image), illustrating the typical low‐frequency pacemaker activity (black trace, mV). Lower blue trace depicts parallel 2‐photon laser scanning fluo‐4 Ca2+ imaging of the same neuron, illustrating the dendritic Ca2+ oscillations (∆G/R), that are fully blocked by the L‐type Ca2+ channel blocker isradipine particularly in the proximal dendrites, while activity of SN DA neurons remains largely unaffected (figure adapted from and methods detailed in Guzman et al. 2010). Lower: Cartoon illustrating distinct ion channels, receptors and transporters that generate or modulate the activity patterns of SN DA neurons in vivo and in vitro, and that are associated with oscillating Ca2+ levels and signaling pathways, affecting mitochondrial and lysosomal function as well as gene expression in health and in Parkinson's disease, (see text for details). Note that only a selection of ion channels that are expressed in SN DA neurons is depicted. Voltage‐gated LTCCs (particular of the Cav1.3 type) as well as metabolically gated K‐ATP channels (of the Kir6.2/SUR1 type) seem to be crucial for physiological SN DA function, but have both also been linked to SN DA degeneration and PD. Abbreviations: A‐type Kv/KChip: A‐type voltage‐gated K+ channel; CREB: cAMP response element‐binding protein; D2‐AR: dopamine D2 autoreceptor; DJ‐1: PARK7 gene product; DREAM: DRE antagonist modulator; ER: endoplasmatic reticulum; ETC: electron transport chain; GBA: glucocerebrosidase; GIRK: G‐protein‐coupled inwardly rectifying K+ channel; GRK2: G‐protein‐dependent kinase 2; IP3R: inositol‐3‐phosphate receptor; K‐ATP: ATP‐sensitive K+ channel; LETM1: high Ca2+ affine leucine zipper EF‐hand containing transmembrane protein 1; LTCC (Cav1.3): Cav1.3 L‐type voltage‐gated Ca2+ channel; mCU: mitochondrial Ca2+ uniporter; MNCX: mitochondrial Na+/Ca2+ exchanger; mPTP: mitochondrial permeability transition pore; NCS‐1: neuronal Ca2+ sensor 1; NCX: Na+/Ca2+ exchanger; NMDA‐R: N‐methyl‐D‐aspartate glutamate receptor; OXPHOS: oxidative phosphorylation; P: phosphate; PD: Parkinson's disease; PMCA: plasma membrane Ca2+ ATPase; ROS: reactive oxygen species; RyR: ryanodine receptor; SERCA: sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase; SK: small conductance Ca2+ sensitive K+ channel; STIM: stromal interaction molecule; TCA: tricarboxylic acid cycle, TRP: transient receptor potential; TTCC: T‐type voltage‐gated Ca2+ channel; UCP: uncoupling protein.
Figure 2
Figure 2
Double‐edged roles of activity and free intracellular Ca2+ levels for physiological functions of SN DA neurons and their vulnerability to PD‐triggers. Shown are typical in vivo and in vitro single‐spike activity patterns of SN DA neurons from adult mice (adapted from Dragicevic et al. 2015; methods detailed in Schiemann et al. 2012; Dragicevic et al. 2014). Note that the important – and energy demanding – burst activity mode of SN DA neurons is not shown. The cartoon summarizes that SN DA neurons possess several intrinsic feedback and feed‐forward mechanisms to protect and to adapt their activity pattern as well as their oscillatory calcium homeostasis (crucial for dopamine release, and metabolic homeostasis) in both directions within a physiological bandwidth (indicated by green arrows/color and black dotted lines). Both, reduced as well as elevated activity and associated calcium homeostasis can trigger SN DA degeneration, as indicated by ‘use it or lose it’ and ‘excitotoxicity’. PD‐trigger factors could narrow the physiological bandwidth of these two parameters, and thus facilitate pathophysiological and degenerative pathways (indicated by red arrows/color and red dotted lines). VGCCs as well as K‐ATP channels are from particular importance, as they have bidirectional physiological functions, can stimulate each other's activity (indicated by dotted gray double‐arrow), and they both can trigger selective SN DA degeneration and PD (compare figure 1, for details see text). Abbreviations: K‐ATP: ATP‐sensitive potassium channel; PARK‐gene: Parkinson's disease associated gene; PD: Parkinson's disease; VGCCs: voltage‐gated calcium channels.

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