The Role of Voltage-Gated Calcium Channels in Basal Ganglia Neurodegenerative Disorders

Abstract

Calcium (Ca²⁺) plays a central role in regulating many cellular processes and influences cell survival. Several mechanisms can disrupt Ca²⁺ homeostasis to trigger cell death, including oxidative stress, mitochondrial damage, excitotoxicity, neuroinflammation, autophagy, and apoptosis. Voltage-gated Ca²⁺ channels (VGCCs) act as the main source of Ca²⁺ entry into electrically excitable cells, such as neurons, and they are also expressed in glial cells such as astrocytes and oligodendrocytes. The dysregulation of VGCC activity has been reported in both Parkinson's disease (PD) and Huntington's (HD). PD and HD are progressive neurodegenerative disorders (NDs) of the basal ganglia characterized by motor impairment as well as cognitive and psychiatric dysfunctions. This review will examine the putative role of neuronal VGCCs in the pathogenesis and treatment of central movement disorders, focusing on PD and HD. The link between basal ganglia disorders and VGCC physiology will provide a framework for understanding the neurodegenerative processes that occur in PD and HD, as well as a possible path towards identifying new therapeutic targets for the treatment of these debilitating disorders.

Keywords: Calcium channels; basal ganglia and cell death; huntington’s disease; neurodegenerative disorders; parkinson’s disease.

Fig. (1)

Schematic representation of VGCCs. HVA channels consist of a pore-forming α1 subunit that coassembles with ancillary β, α2δ, and γ subunits, plus calmodulin (CaM). The α1 subunit is a transmembrane protein composed of four repeated amino acid sequence domains (I-IV), with each containing six transmembrane segments (S1-S6). The intracellular β subunit has no transmembrane segments, while the γ subunit is a glycoprotein with four transmembrane segments. The α2 subunit is an extracellular glycoprotein attached to the membrane by the δ subunit. LVA channels function as α1 subunit monomers.

Fig. (2)

Mechanisms of cell death triggered by Ca²⁺ in a dopaminergic neuron: Ca²⁺ is finely regulated by intercellular and intracellular signaling mechanisms, which are fundamental for survival and death in biological organisms. Ca²⁺ mainly enters the cytoplasm through ligand-gated channels, such as glutamate receptors, VGCCs, and store-operated channels. Ca²⁺ efflux is regulated primarily by the plasma-membrane Ca²⁺-ATPase (PMCA) and the Na⁺/ Ca²⁺-exchanger (NCX). The largest Ca²⁺ store in the cell is found in the ER, and its concentration is modulated by sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) pumps, inositol-1, 4, 5- trisphosphate (Ins(1, 4, 5)P3) receptors (Ins(1, 4, 5)P3 Rs), and ryanodine receptors (RYRs) as well as by Ca²⁺ -binding proteins. Mitochondria take up Ca²⁺ via the mitochondrial uniporter (mUP), and can release it through the reversal of the uniporter, Na⁺/Ca²⁺ exchanger, or by the permeability transition pore (PTP) opening. As discussed in the text, excessive Ca²⁺ influx through VGCCs may trigger several mechanisms of cell damage, which results in a cascade of interconnected cellular dysfunction, including (1) excitotoxicity; (2) mitochondrial dysfunction and fragmentation, leading to the generation of ROS, cytochrome C release, and subsequent apoptotic cell death; (3) neuroinflammation, facilitated by the microglia-mediated release of neurotoxic factors and ROS, leading to autonomous neurotoxicity mechanisms; (4) a depletion in ATP and reduction in ATP-dependent processes, such as autophagic clearance of damaged proteins and organelles regulated by the ubiquitin-proteasome system (UPS); and (5) DNA damage, which activates apoptosis cascades. In addition, activating the L-type Ca²⁺ channel may increase its intracellular concentration and activate calpains, leading to the inhibition of autophagy (6), a fundamental process for excluding damaged proteins and organelles. As illustrated, these processes are interconnected and can occur simultaneously.

Fig. (3)

Pathogenic cellular mechanisms in PD and HD. A. PD is characterized by a degeneration of dopaminergic neurons in the SNpc of the midbrain and the development of neuronal Lewy Body accumulation in neurons. The schematic representation shows the main mechanisms that lead to cell death in PD - aggregation of Lewy Bodies is associated with a process related to mitochondrial dysfunction, which is a key element in the pathogenesis of PD. Such a process can be precipitated by excessive Ca²⁺ input by VGCCs, whose inhibition by dihydropyridines (DHPs) has been shown to play an important role in managing the evolution of neuronal degeneration. B. HD is a neurodegenerative disorder whose mechanism involves the accumulation of mutated huntingtin protein (mHtt), followed by the death of GABAergic neurons. The neuronal cell loss in HD is associated with glutamatergic excitotoxicity, mediated by an excessive influx of intracellular Ca²⁺, N-type Ca²⁺ channels (Ca_v2.2), and L-type Ca²⁺ channels (Ca_v1.2), which are affected by mHtt. Furthermore, L-type channels can be inhibited by the ER STIM1 and DHPs.