Dopamine midbrain neurons in health and Parkinson's disease: emerging roles of voltage-gated calcium channels and ATP-sensitive potassium channels (original) (raw)
Related papers
Vulnerability of mesostriatal dopaminergic neurons in Parkinson’s disease
Frontiers in Neuroanatomy, 2010
The term vulnerability was first associated with the midbrain dopaminergic neurons 85 years ago, before they were identified as monoaminergic neurons, when Foix and Nicolesco (1925) reported the loss of neuromelanin containing neurons in the midbrain of patients with postencephalitic Parkinson's disease (PD). A few years later, Hassler (1938) showed that degeneration is more intense in the ventral tier of the substantia nigra compacta than in its dorsal tier and the ventral tegmental area (VTA), outlining the concept of differential vulnerability of midbrain dopaminergic (DA-) neurons. Nowadays, we know that other neuronal groups degenerate in PD, but the massive loss of nigral DA-cells is its pathological hallmark, having a pivotal position in the pathophysiology of the disease as it is responsible for the motor symptoms. Data from humans as well as cellular and animal models indicate that DA-cell degeneration is a complex process, probably precipitated by the convergence of different risk factors, mediated by oxidative stress, and involving pathogenic factors arising within the DA-neuron (intrinsic factors), and from its environment and distant interconnected brain regions (extrinsic factors). In light of current data, intrinsic factors seem to be preferentially involved in the first steps of the degenerative process, and extrinsic factors in its progression. A controversial issue is the relative weight of the impairment of common cell functions, such as energy metabolism and proteostasis, and specific dopaminergic functions, such as pacemaking activity and DA handling, in the pathogenesis of DA-cell degeneration. Here we will review the current knowledge about the relevance of these factors at the beginning and during the progression of PD, and in the differential vulnerability of midbrain DA-cells.
The Journal of physiology, 2015
The voltage-gated Ca(2+) channels (VGCCs) that catalyse striatal dopamine transmission are critical to dopamine function and might prime subpopulations of neurons for parkinsonian degeneration. However, the VGCCs that operate on mesostriatal axons are incompletely defined; previous studies encompassed channels on striatal cholinergic interneurons that strongly influence dopamine transmission. We define that multiple types of axonal VGCCs operate that extend beyond classic presynaptic N/P/Q channels to include T- and L-types. We reveal differences in VGCC function between mouse axon types that in humans are vulnerable versus resistant to Parkinson's disease. We show for the first time that this is underpinned by different sensitivity of dopamine transmission to extracellular Ca(2+) and by different spatiotemporal intracellular Ca(2+) microdomains. These data define key principles of how Ca(2+) and VGCCs govern dopamine transmission in the healthy brain and reveal differences betw...
, especially the Cav1.3-subtype, generate an activity-related oscillatory Ca 2+ burden in SN DA neurons, contributing to their degeneration and PD. While LTCC-blockers are already in clinical trials as PDtherapy, age-dependent functional roles of Cav1.3 LTCCs in SN DA neurons remain unclear. Thus, we analysed juvenile and adult Cav1.3-deficient mice with electrophysiological and molecular techniques. To unmask compensatory effects, we compared Cav1.3 KO mice with pharmacological LTCC-inhibition. LTCC-function was not necessary for SN DA pacemaker-activity at either age, but rather contributed to their pacemaker-precision. Moreover, juvenile Cav1.3 KO but not WT mice displayed adult wildtypelike, sensitised inhibitory dopamine-D2-autoreceptor (D2-AR) responses that depended upon both, interaction of the neuronal calcium sensor NCS-1 with D2-ARs, and on voltage-gated T-type calcium channel (TTCC) activity. This functional KO-phenotype was accompanied by cell-specific up-regulation of NCS-1 and Cav3.1-TTCC mRNA. Furthermore, in wildtype we identified an age-dependent switch of TTCC-function from contributing to SN DA pacemaker-precision in juveniles to pacemaker-frequency in adults. This novel interplay of Cav1.3 L-type and Cav3.1 T-type channels, and their modulation of SN DA activity-pattern and D2-AR-sensitisation, provide new insights into flexible age-and calciumdependent activity-control of SN DA neurons and its pharmacological modulation.
Experimental Neurology, 2008
Tyrosine hydroxylase SK Parkinson's disease (PD) is characterized by loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). It is widely believed that replacing lost SNc DA neurons is a key to longer-term effective treatment of PD motor symptoms, but generating new SNc DA neurons in PD patients has proven difficult. Following loss of tyrosine hydroxylase-positive (TH+) SNc neurons in the rodent 6-hydroxy-DA (6-OHDA) model of PD, the number of TH+ neurons partially recovers and there is evidence this occurs via phenotype "shift" from TH− to TH+ cells. Understanding how this putative phenotype shift occurs may help increase SNc DAergic neurons in PD patients. In this study we characterize the electrophysiology of SNc TH− and TH+ cells during recovery from 6-OHDA in mice. Three distinct phenotypes were observed: (1) TH− were fast discharging with a short duration action potential (AP), short afterhyperpolarization (AHP) and no small conductance Ca 2+ -activated K + (SK) current; (2) TH+ were slow discharging with a long AP, long AHP and prominent SK current; and (3) cells with features "intermediate" between these TH− and TH+ phenotypes. The same 3 phenotypes were present also in the normal and D2 DA receptor knock-out SNc suggesting they are more closely related to the biology of TH expression than recovery from 6-OHDA. Acute inhibition of SK channel function shifted the electrophysiological phenotype of TH+ neurons toward TH− and chronic (2 weeks) inhibition of SK channel function in normal mice shifted the neurochemical phenotype of SNc from TH+ to TH− (i.e. decreased TH+ and increased TH− cell numbers). Importantly, chronic facilitation of SK channel function shifted the neurochemical phenotype of SNc from TH− to TH+ (i.e. increased TH+ and decreased TH− cell numbers). We conclude that SK channel function bidirectionally regulates the DA phenotype of SNc cells and facilitation of SK channels may be a novel way to increase the number of SNc DAergic neurons in PD patients.
Cellular and Synaptic Dysfunctions in Parkinson’s Disease: Stepping out of the Striatum
Cells
The basal ganglia (BG) are a collection of interconnected subcortical nuclei that participate in a great variety of functions, ranging from motor programming and execution to procedural learning, cognition, and emotions. This network is also the region primarily affected by the degeneration of midbrain dopaminergic neurons localized in the substantia nigra pars compacta (SNc). This degeneration causes cellular and synaptic dysfunctions in the BG network, which are responsible for the appearance of the motor symptoms of Parkinson’s disease. Dopamine (DA) modulation and the consequences of its loss on the striatal microcircuit have been extensively studied, and because of the discrete nature of DA innervation of other BG nuclei, its action outside the striatum has been considered negligible. However, there is a growing body of evidence supporting functional extrastriatal DA modulation of both cellular excitability and synaptic transmission. In this review, the functional relevance of ...
The Journal of Neuroscience
Ca 2ϩ-influx through L-type Ca 2ϩ-channels (LTCCs) is associated with activity-related stressful oscillations of Ca 2ϩ levels within dopaminergic (DA) neurons in the substantia nigra (SN), which may contribute to their selective degeneration in Parkinson's disease (PD). LTCC blockers were neuroprotective in mouse neurotoxin models of PD, and isradipine is currently undergoing testing in a phase III clinical trial in early PD. We report no evidence for neuroprotection by in vivo pretreatment with therapeutically relevant isradipine plasma levels, or Ca v 1.3 LTCC deficiency in 6-OHDA-treated male mice. To explain this finding, we investigated the pharmacological properties of human LTCCs during SN DA-like and arterial smooth muscle (aSM)-like activity patterns using whole-cell patch-clamp recordings in HEK293 cells (Ca v 1.2 ␣1-subunit, long and short Ca v 1.3 ␣1-subunit splice variants; 3/␣2␦1). During SN DA-like pacemaking, only Ca v 1.3 variants conducted Ca 2ϩ current (I Ca) at subthreshold potentials between action potentials. SN DA-like burst activity increased integrated I Ca during (Ca v 1.2 plus Ca v 1.3) and after (Ca v 1.3) the burst. Isradipine inhibition was splice variant and isoform dependent, with a 5to 11-fold lower sensitivity to Ca v 1.3 variants during SN DA-like pacemaking compared with Ca v 1.2 during aSM-like activity. Supratherapeutic isradipineconcentrationsreducedthepacemakerprecisionofadultmouseSNDAneuronsbutdidnotaffecttheirsomaticCa 2ϩ oscillations.Our data predict that Ca v 1.2 and Ca v 1.3 splice variants contribute differentially to Ca 2ϩ load in SN DA neurons, with prominent Ca v 1.3-mediated I Ca between action potentials and after bursts. The failure of therapeutically relevant isradipine levels to protect SN DA neurons can be explained by weaker state-dependent inhibition of SN DA LTCCs compared with aSM Ca v 1.2.
Calcium, Dopamine and Neuronal Calcium Sensor 1: Their Contribution to Parkinson’s Disease
Frontiers in Molecular Neuroscience, 2019
Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra pars compacta. The causes of PD in humans are still unknown, although metabolic characteristics of the neurons affected by the disease have been implicated in their selective susceptibility. Mitochondrial dysfunction and proteostatic stress are recognized to be important in the pathogenesis of both familial and sporadic PD, and they both culminate in bioenergetic deficits. Exposure to calcium overload has recently emerged as a key determinant, and pharmacological treatment that inhibits Ca 2+ entry diminishes neuronal damage in chemical models of PD. In this review, we first introduce general concepts on neuronal Ca 2+ signaling and then summarize the current knowledge on fundamental properties of substantia nigra pars compacta dopaminergic neurons, on the role of the interplay between Ca 2+ and dopamine signaling in neuronal activity and susceptibility to cell death. We also discuss the possible involvement of a "neglected" player, the Neuronal Calcium Sensor-1 (NCS-1), which has been shown to participate to dopaminergic signaling by regulating dopamine dependent receptor desensitization in normal brain but, data supporting a direct role in PD pathogenesis are still missing. However, it is intriguing to speculate that the Ca 2+-dependent modulation of NCS-1 activity could eventually counteract dopaminergic neurons degeneration.
Journal of Neurophysiology, 2008
The activity patterns of subthalamic nucleus (STN) neurons are intimately related to motor function/dysfunction and modulated directly by dopaminergic neurons that degenerate in Parkinson's disease (PD). To understand how dopamine and dopamine depletion influence the activity of the STN, the functions/signaling pathways/substrates of D2-like dopamine receptors were studied using patch-clamp recording. In rat brain slices, D2-like dopamine receptor activation depolarized STN neurons, increased the frequency/irregularity of their autonomous activity, and linearized/enhanced their firing in response to current injection. Activation of D2-like receptors in acutely isolated neurons reduced transient outward currents evoked by suprathreshold voltage steps. Modulation was inhibited by a D2-like receptor antagonist and occluded by voltage-dependent Ca2+(Cav) channel or small-conductance Ca2+-dependent K+(SKCa) channel blockers or Ca2+-free media. Because Cavchannels are targets of Gi/o-...
The Journal of Neuroscience, 2017
Ca 2ϩ-influx through L-type Ca 2ϩ-channels (LTCCs) is associated with activity-related stressful oscillations of Ca 2ϩ levels within dopaminergic (DA) neurons in the substantia nigra (SN), which may contribute to their selective degeneration in Parkinson's disease (PD). LTCC blockers were neuroprotective in mouse neurotoxin models of PD, and isradipine is currently undergoing testing in a phase III clinical trial in early PD. We report no evidence for neuroprotection by in vivo pretreatment with therapeutically relevant isradipine plasma levels, or Ca v 1.3 LTCC deficiency in 6-OHDA-treated male mice. To explain this finding, we investigated the pharmacological properties of human LTCCs during SN DA-like and arterial smooth muscle (aSM)-like activity patterns using whole-cell patch-clamp recordings in HEK293 cells (Ca v 1.2 ␣1-subunit, long and short Ca v 1.3 ␣1-subunit splice variants; 3/␣2␦1). During SN DA-like pacemaking, only Ca v 1.3 variants conducted Ca 2ϩ current (I Ca) at subthreshold potentials between action potentials. SN DA-like burst activity increased integrated I Ca during (Ca v 1.2 plus Ca v 1.3) and after (Ca v 1.3) the burst. Isradipine inhibition was splice variant and isoform dependent, with a 5to 11-fold lower sensitivity to Ca v 1.3 variants during SN DA-like pacemaking compared with Ca v 1.2 during aSM-like activity. Supratherapeutic isradipineconcentrationsreducedthepacemakerprecisionofadultmouseSNDAneuronsbutdidnotaffecttheirsomaticCa 2ϩ oscillations.Our data predict that Ca v 1.2 and Ca v 1.3 splice variants contribute differentially to Ca 2ϩ load in SN DA neurons, with prominent Ca v 1.3-mediated I Ca between action potentials and after bursts. The failure of therapeutically relevant isradipine levels to protect SN DA neurons can be explained by weaker state-dependent inhibition of SN DA LTCCs compared with aSM Ca v 1.2.