Dopamine midbrain neurons in health and Parkinson’s disease: Emerging roles of voltage-gated calcium channels and ATP-sensitive potassium channels

Abstract

Dopamine (DA) releasing midbrain neurons are essential for multiple brain functions, such as voluntary movement, working memory, emotion and cognition. DA midbrain neurons within the substantia nigra (SN) and the ventral tegmental area (VTA) exhibit a variety of distinct axonal projections and cellular properties, and are differentially affected in diseases like schizophrenia, attention deficit hyperactivity disorder, and Parkinson's disease (PD). Apart from having diverse functions in health and disease states, DA midbrain neurons display distinct electrical activity patterns, crucial for DA release. These activity patterns are generated and modulated by specific sets of ion channels. Recently, two ion channels have been identified, not only contributing to these activity patterns and to functional properties of DA midbrain neurons, but also seem to render SN DA neurons particularly vulnerable to degeneration in PD and its animal models: L-type calcium channels (LTCCs) and ATP-sensitive potassium channels (K-ATPs). In this review, we focus on the emerging physiological and pathophysiological roles of these two ion channels (and their complex interplay with other ion channels), particularly in highly vulnerable SN DA neurons, as selective degeneration of these neurons causes the major motor symptoms of PD.

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

“…After MPTP treatment, local elevation of N/OFQ levels may inhibit the release of GABA in SNr and elevate local Glu levels to neurotoxic levels in the SNc DA neurons whose dendrites are extensively distributed throughout the SNr. The SNc DA neurons are known to be particularly sensitive to calcium toxicity (Dragicevic et al, 2015). Collectively these results point to a role for endogenous N/OFQ in the SNr, acting through NOP receptors, in dysregulating local control of both Glu and GABA concentrations, particularly when endogenous DA is depleted, with deleterious effects on both the SNc DA neurons and on the nigrothalamic output pathway of the SNr (see Fig.…”

Somatodendritic dopamine release: recent mechanistic insights

“…B 370: 20140185 with neuronal properties [103]. Similarly, the activity of K ATP channels in DA neurons in medial SNc regulates burst firing in these cells, which in turn contributes to exploratory behaviour in animals placed in a novel environment [92,94].…”

Investigating the role of Sirt1-modulated oxidative stress in relation to benign paroxysmal positional vertigo and Parkinson's disease

“…Dominique Vibert et al suggested animals with bilateral ovariectomy change the structure of otoconia and the turnover of calcium (Vibert et al, 2008). In patients with PD, an imbalanced calcium concentration has been identified in neurons (Dragicevic et al, 2015). Moreover, calcium signaling is modulated by oxidative stress and free radicals.…”