title: Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons.
abstract: Dopamine midbrain neurons within the substantia nigra are particularly prone to degeneration in Parkinson's disease. Their selective loss causes the major motor symptoms of Parkinson's disease, but the causes for the high vulnerability of SN DA neurons, compared to neighbouring, more resistant ventral tegmental area dopamine neurons, are still unclear. Consequently, there is still no cure available for Parkinson's disease. Current therapies compensate the progressive loss of dopamine by administering its precursor l-DOPA and/or dopamine D2-receptor agonists. D2-autoreceptors and Cav1.3-containing L-type Ca(2+) channels both contribute to Parkinson's disease pathology. L-type Ca(2+) channel blockers protect SN DA neurons from degeneration in Parkinson's disease and its mouse models, and they are in clinical trials for neuroprotective Parkinson's disease therapy. However, their physiological functions in SN DA neurons remain unclear. D2-autoreceptors tune firing rates and dopamine release of SN DA neurons in a negative feedback loop through activation of G-protein coupled potassium channels (GIRK2, or KCNJ6). Mature SN DA neurons display prominent, non-desensitizing somatodendritic D2-autoreceptor responses that show pronounced desensitization in PARK-gene Parkinson's disease mouse models. We analysed surviving human SN DA neurons from patients with Parkinson's disease and from controls, and detected elevated messenger RNA levels of D2-autoreceptors and GIRK2 in Parkinson's disease. By electrophysiological analysis of postnatal juvenile and adult mouse SN DA neurons in in vitro brain-slices, we observed that D2-autoreceptor desensitization is reduced with postnatal maturation. Furthermore, a transient high-dopamine state in vivo, caused by one injection of either l-DOPA or cocaine, induced adult-like, non-desensitizing D2-autoreceptor responses, selectively in juvenile SN DA neurons, but not ventral tegmental area dopamine neurons. With pharmacological and genetic tools, we identified that the expression of this sensitized D2-autoreceptor phenotype required Cav1.3 L-type Ca(2+) channel activity, internal Ca(2+), and the interaction of the neuronal calcium sensor NCS-1 with D2-autoreceptors. Thus, we identified a first physiological function of Cav1.3 L-type Ca(2+) channels in SN DA neurons for homeostatic modulation of their D2-autoreceptor responses. L-type Ca(2+) channel activity however, was not important for pacemaker activity of mouse SN DA neurons. Furthermore, we detected elevated substantia nigra dopamine messenger RNA levels of NCS-1 (but not Cav1.2 or Cav1.3) after cocaine in mice, as well as in remaining human SN DA neurons in Parkinson's disease. Thus, our findings provide a novel homeostatic functional link in SN DA neurons between Cav1.3- L-type-Ca(2+) channels and D2-autoreceptor activity, controlled by NCS-1, and indicate that this adaptive signalling network (Cav1.3/NCS-1/D2/GIRK2) is also active in human SN DA neurons, and contributes to Parkinson's disease pathology. As it is accessible to pharmacological modulation, it provides a novel promising target for tuning substantia nigra dopamine neuron activity, and their vulnerability to degeneration.
authors.affiliation: 1 Institute of Applied Physiology, University of Ulm, Ulm, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Dragicevic
authors.affiliation: 1 Institute of Applied Physiology, University of Ulm, Ulm, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Poetschke
authors.affiliation: 1 Institute of Applied Physiology, University of Ulm, Ulm, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Duda
authors.affiliation: 1 Institute of Applied Physiology, University of Ulm, Ulm, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Schlaudraff
authors.affiliation: 2 Nancy Pritzker Laboratory, Department of Psychiatry and Behavioural Sciences, Stanford University School of Medicine, Palo Alto, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Lammel
authors.affiliation: 3 Institute of Neurophysiology, Goethe University Frankfurt, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schiemann
authors.affiliation: 1 Institute of Applied Physiology, University of Ulm, Ulm, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Fauler
authors.affiliation: 4 Rosalind Franklin University of Medicine and Science, North Chicago, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hetzel
authors.affiliation: 5 Department of Anatomy, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: 6 Instituto de Investigación en Discapacidades Neurológicas (IDINE), Departamento de Ciencias Médicas, Universidad Castilla-La Mancha, Albacete, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Lujan
authors.affiliation: 2 Nancy Pritzker Laboratory, Department of Psychiatry and Behavioural Sciences, Stanford University School of Medicine, Palo Alto, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Malenka
authors.affiliation: 7 Institute of Pharmacy, Department of Pharmacology and Toxicology, Centre of Molecular Biosciences, University of Innsbruck, Austria.
authors.forename: Joerg
authors.initials: J
authors.lastname: Striessnig
authors.affiliation: 1 Institute of Applied Physiology, University of Ulm, Ulm, Germany birgit.liss@uni-ulm.de.
authors.forename: Birgit
authors.initials: B
authors.lastname: Liss
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D059290:Dopaminergic Neurons / Q000378:metabolism*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051580:Neuronal Calcium-Sensor Proteins / Q000502:physiology*; D009479:Neuropeptides / Q000502:physiology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000378:metabolism* / Q000473:pathology
chemical_list: D017660:Autoreceptors; C472073:CACNA1D protein, human; C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C094401:KCNJ6 protein, human; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; D017448:Receptors, Dopamine D2; C101464:frequenin calcium sensor proteins
keywords: D2-autoreceptor; Parkinsons disease; cocaine; isradipine; l-DOPA