Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons
| Autor: | Christina Poetschke, Andrea Hetzel, Elena Dragicevic, Joerg Striessnig, Birgit Liss, Johanna Duda, Rafael Luján, Stephan Lammel, Robert C. Malenka, Falk Schlaudraff, Masahiko Watanabe, Michael Fauler, Julia Schiemann |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Inbred C57BL Cav1.3 Mice Parkinsons disease Receptors Autoreceptors Mice Knockout biology L-Dopa isradipine L-Type Parkinson disease Ventral tegmental area medicine.anatomical_structure Calcium channels L-type Basal ganglia Pacemaking medicine.drug medicine.medical_specialty Knockout Neuronal Calcium-Sensor Proteins CA2+ channels cocaine Substantia nigra Gated potassium channels Neuroprotection Midbrain Dopamine Internal medicine Dopamine D2 medicine Animals Humans Calcium Signaling ddc:610 Medium spiny neurons Receptors Dopamine D2 Dopaminergic Neurons Neuropeptides Ventral Tegmental Area D2-autoreceptor Scientific Commentaries Mice Inbred C57BL Calciumkanal Electrophysiology Endocrinology G Protein-Coupled Inwardly-Rectifying Potassium Channels nervous system Protein-coupled receptor biology.protein Calcium Channels Neurology (clinical) Neuron DDC 610 / Medicine & health Neuroscience |
| Zdroj: | Brain: a journal of neurology, vol 137, iss Pt 8 |
| ISSN: | 1460-2156 0006-8950 |
| Popis: | 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 Ca2+ channels both contribute to Parkinson’s disease pathology. L-type Ca2+ 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 Ca2+ channel activity, internal Ca2+, 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 Ca2+ channels in SN DA neurons for homeostatic modulation of their D2-autoreceptor responses. L-type Ca2+ 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-Ca2+ 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. publishedVersion |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|