Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease

Abstract

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

Lower Affinity of Isradipine for L-Type Ca2+ Channels during Substantia Nigra Dopamine Neuron-Like Activity: Implications for Neuroprotection in Parkinson's Disease

“…Pumps were loaded with ISR dissolved in vehicle [dimethylsulfoxide (DMSO)/ PEG300]. Neuroprotective effects of ISR were assessed only in mice in which plasma concentrations of ISR Ͼ3 ng/ml were reached that correspond to human therapeutic steady-state plasma levels [Christensen et al, 2000;Park et al, 2009;Wang et al, 2013; SPC Lomir (compendium.ch/mpro/mnr/ 2604/html/)]. ISR mouse plasma concentrations were measured by liquid chromatography-tandem mass spectrometry.…”

“…The primary motor symptoms reflect the progressive loss of dopaminergic (DA) neurons, particularly within the substantia nigra (SN;Hurley and Dexter, 2012;Sulzer and Surmeier, 2013). These neurons constantly fire action potentials (APs; Grace and Bunney, 1984a,b;Puopolo et al, 2007), resulting in an oscillatory Ca 2ϩ influx throughout the dendrites and the soma (Chan et al, 2007). The metabolically challenging task to remove Ca 2ϩ from the cytosol increases SN DA mitochondrial oxidative stress (Guzman et al, 2009, rendering them more vulnerable to degeneration (for reviews see Surmeier et al, 2012;.…”

“…L-type voltage-gated Ca 2ϩ channels [LTCCs (Ca v 1); Catterall et al, 2005] are required for normal endocrine, brain, sensory, and muscle function , and brain Ca v 1.2 and Ca v 1.3 channels are also expressed by SN DA neurons (Olson et al, 2005;Dragicevic et al, 2014;Philippart et al, 2016;Sun et al, 2017). Ca v 1.3 channels can open at subthreshold membrane potentials due to their negative activation voltage range (Koschak et al, 2001;Xu and Lipscombe, 2001;Lieb et al, 2014) and are thus postulated to be a major contributor to mitochondrial stress-inducing Ca 2ϩ oscillations in SN DA neurons Hurley and Dexter, 2012;Hurley et al, 2013;Sulzer and Surmeier, 2013;Branch et al, 2014).…”

“…Ca v 1.3 channels can open at subthreshold membrane potentials due to their negative activation voltage range (Koschak et al, 2001;Xu and Lipscombe, 2001;Lieb et al, 2014) and are thus postulated to be a major contributor to mitochondrial stress-inducing Ca 2ϩ oscillations in SN DA neurons Hurley and Dexter, 2012;Hurley et al, 2013;Sulzer and Surmeier, 2013;Branch et al, 2014). Reducing LTCC activity using specific blockers is currently being pursued as a new neuroprotective strategy .…”

“…Although human epidemiological studies indicate a 20 -30% lower risk of the development of PD in patients treated with nonselective brain-permeant DHP channel blockers for references), preclinical in vivo studies with DHP channel blockers in PD animal models are controversial. For example, several studies report DHP-mediated protection of SN DA neurons (Kupsch et al, 1995(Kupsch et al, , 1996Chan et al, 2007;Meredith et al, 2008;, but others have failed to confirm these findings (Sautter et al, 1997). Although differences in experimental design may explain some of these discrepancies, it remains unclear whether brain Ca v 1.2 and Ca v 1.3 channels are inhibited as effectively as aSM Ca v 1.2 channels at doses of DHP channel blockers used for chronic DHP treatment.…”