Cell Signaling in Chronic CNS Disorders: TP12 - Functional role of L-Type Ca2+-channels in dopaminergic midbrain neurons in health and disease states.

• Applicant: Professorin Dr. Birgit Liss
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2011 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 193706960

Dopamine midbrain neurons within the Substantia nigra (SN DA) are particularly prone to degeneration in Parkinson¿s disease (PD). Understanding the molecular mechanisms of SN DA function and signaling in health and disease is the prerequisite for the development of novel neuroprotective PD-therapies. Bood-brain-barrier permeant L-type Ca2+ channel (LTCC) blockers are already in clinical trials for neuroprotective PD-therapy. However, our understanding of the functional roles of LTCCs and of the related Ca2+ signaling for SN DA neurons and for their degeneration and PD-pathology is still fragmentary,In the 1st funding-period, we identified the neuronal Ca2+ sensor NCS-1 as a novel link between Cav1.3 LTCCs and dopamine D2-autoreceptors (D2-AR, Girk2 K+ channel coupled), both contributing to PD-pathology. Our findings demonstrate that a novel Cav1.3/NCS-1/D2-AR/Girk2 signaling network is tuning age- and dopamine-dependent SN DA activity, crucial for their dopamine release, in response to in vivo changes in extracellular dopamine levels in mice (induced by cocaine or L-DOPA), via functional expression of NCS-1 - which could also be translated to human PD pathology. Our findings point to a homeostatic role of this signaling network (in unclear interplay with other voltage gated ion channels) for adaptive changes in SN DA activity due to altered dopamine levels. This offers promising novel targets for specific pharmacological modulation of SN DA activity, as well as of their vulnerability to degeneration in PD. Consequently, in the 2nd SFB-funding, we aim on further analyze this novel SN DA Cav1.3/NCS-1/D2-AR signaling. In particular, by utilizing specific mouse models and drugs, provided within this SFB, we will further define and dissect: (1) the distinct induction- and modulation-scenarios, (2) the underlying molecular mechanisms, in particular in interplay with other voltage gated ion channels, and (3) the essential acute and chronic (patho-) physiological consequences of Cav1.3/NCS-1/D2-AR signaling and its modulation in SN DA neurons in context of PD. We will analyze electrophysiological functions and contributions of distinct ion channels in mouse DA neurons in vitro as well as in vivo. We will molecularly define underlying signaling mechanisms via cell-specific gene- and protein-expression analysis in mouse and human SN DA neurons (PD vs. controls). Our proposed dissection of Cav1.3, Ca2+ and NCS-1 for SN DA D2-AR activity-tuning, in interplay with other channels, provides an important molecular step towards a better understanding of LTCC function in these neurons, and thus for tailored pharmacological neuroprotective therapy. It will likely provide novel, cell-specific molecular pathways and targets for tuning SN DA activity and their vulnerability to degeneration in PD and aging.

• DFG Programme: Research Grants
• International Connection: Austria
• Major Instrumentation: Recording Set up
• Instrumentation Group: 3440 Elektrophysiologische Meßsysteme (außer 300-309 und 340-343)
• Cooperation Partner: Professor Dr. Jörg Striessnig