Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease

Abstract

Degeneration of dopaminergic neurons in the substantia nigra causes the motor symptoms of Parkinson’s disease. The mechanisms underlying this age-dependent and region-selective neurodegeneration remain unclear. Here we identify Cav2.3 channels as regulators of nigral neuronal viability. Cav2.3 transcripts were more abundant than other voltage-gated Ca2+ channels in mouse nigral neurons and upregulated during aging. Plasmalemmal Cav2.3 protein was higher than in dopaminergic neurons of the ventral tegmental area, which do not degenerate in Parkinson’s disease. Cav2.3 knockout reduced activity-associated nigral somatic Ca2+ signals and Ca2+-dependent after-hyperpolarizations, and afforded full protection from degeneration in vivo in a neurotoxin Parkinson’s mouse model. Cav2.3 deficiency upregulated transcripts for NCS-1, a Ca2+-binding protein implicated in neuroprotection. Conversely, NCS-1 knockout exacerbated nigral neurodegeneration and downregulated Cav2.3. Moreover, NCS-1 levels were reduced in a human iPSC-model of familial Parkinson’s. Thus, Cav2.3 and NCS-1 may constitute potential therapeutic targets for combatting Ca2+-dependent neurodegeneration in Parkinson’s disease.

Non-Mendelian inheritance during inbreeding of Cav3.2 and Cav2.3 deficient mice

“…1 in 27 . There is sufficient evidence for a high expression of T-type Ca 2+ channels in embryonic tissues at the molecular level 28 , which appears to be especially important for cardiac 29 , 30 and neuronal development 31 , 32 .…”

A Multi-Scale Computational Model of Excitotoxic Loss of Dopaminergic Cells in Parkinson's Disease

“…It was reported that calcium channels in the SNc neuron contribute to neurodegeneration in PD (Benkert et al, 2019 ). In calcium channel blocker therapy (involving calcium blockers such as dihydropyridine, amlodipine), the excess calcium influx into SNc neurons is blocked by reducing the flux through calcium channels in the proposed model (Ritz et al, 2010 ; Liss and Striessnig, 2019 ).…”

Cav2.3 R-type calcium channels: from its discovery to pathogenic de novo CACNA1E variants: a historical perspective

“…In an in vivo mouse model of Parkinson disease (injection of MPTP/probenecid), Ca v 2.3 was identified as a mediator of SN dopaminergic neuron loss [5]. In adult SN dopaminergic neurons, it was shown that Ca v 2.3 represents the most abundantly expressed voltage-gated Ca 2+ channel subtype.…”

“…In adult SN dopaminergic neurons, it was shown that Ca v 2.3 represents the most abundantly expressed voltage-gated Ca 2+ channel subtype. It was linked with metabolic stress in these neurons or with their degeneration in Parkinson's disease, which may occur by affecting Ca v -mediated Ca 2+ oscillations and/or by changing Ca 2+ -dependent after hyperpolarizations (AHPs) in SN dopaminergic neurons [5].…”