Inhibition of striatal dopamine release by the L-type calcium channel inhibitor isradipine co-varies with risk factors for Parkinson's

by Selleckchem | Feb 11 2024

Ca2+ entry into nigrostriatal dopamine (DA) neurons and axons via L-type voltage-gated Ca2+ channels (LTCCs) contributes, respectively, to pacemaker activity and DA release and has long been thought to contribute to vulnerability to degeneration in Parkinson's disease. LTCC function is greater in DA axons and neurons from substantia nigra pars compacta than from ventral tegmental area, but this is not explained by channel expression level. We tested the hypothesis that LTCC control of DA release is governed rather by local mechanisms, focussing on candidate biological factors known to operate differently between types of DA neurons and/or be associated with their differing vulnerability to parkinsonism, including biological sex, α-synuclein, DA transporters (DATs) and calbindin-D28k (Calb1). We detected evoked DA release ex vivo in mouse striatal slices using fast-scan cyclic voltammetry and assessed LTCC support of DA release by detecting the inhibition of DA release by the LTCC inhibitors isradipine or CP8. Using genetic knockouts or pharmacological manipulations, we identified that striatal LTCC support of DA release depended on multiple intersecting factors, in a regionally and sexually divergent manner. LTCC function was promoted by factors associated with Parkinsonian risk, including male sex, α-synuclein, DAT and a dorsolateral co-ordinate, but limited by factors associated with protection, that is, female sex, glucocerebrosidase activity, Calb1 and ventromedial co-ordinate. Together, these data show that LTCC function in DA axons and isradipine effect are locally governed and suggest they vary in a manner that in turn might impact on, or reflect, the cellular stress that leads to parkinsonian degeneration.

Comments:

This study seems to explore the intricate relationship between L-type voltage-gated calcium channels (LTCCs) in dopamine neurons, focusing on their role in regulating dopamine release and their potential contribution to vulnerability in Parkinson's disease. The findings suggest that LTCCs play a crucial role in controlling dopamine release, particularly in the nigrostriatal pathway, and that this regulation is influenced by various factors.

The research indicates that LTCC function in dopamine neurons might differ between regions (substantia nigra pars compacta vs. ventral tegmental area) and sexes, and it could be influenced by factors associated with either increased vulnerability or protection against Parkinson's disease.

Key findings include:
- LTCCs contribute to pacemaker activity and dopamine release in nigrostriatal neurons.
- LTCC function appears to be higher in substantia nigra pars compacta compared to the ventral tegmental area, despite similar expression levels.
- Factors such as biological sex, α-synuclein, dopamine transporters (DATs), and calbindin-D28k (Calb1) influence LTCC control of dopamine release.
- LTCC support of dopamine release is promoted by factors associated with Parkinsonian risk (e.g., male sex, α-synuclein, DAT, specific coordinates) but limited by factors associated with protection (e.g., female sex, glucocerebrosidase activity, Calb1, different coordinates).

The research suggests that the control of dopamine release by LTCCs is a complex interplay influenced by multiple biological factors, which may contribute to the understanding of the cellular stress mechanisms involved in Parkinson's disease. The regional and sexual divergence in LTCC function highlights the importance of local regulatory mechanisms in modulating dopamine release and its potential implication in disease vulnerability.

This kind of detailed investigation could provide valuable insights into potential targets for therapeutic interventions aimed at modulating dopamine release and managing Parkinson's disease.