Voltage-gated calcium channels and Parkinson's disease

Abstract

A complex interaction of environmental, genetic and epigenetic factors combine with ageing to cause the most prevalent of movement disorders Parkinson's disease. Current pharmacological treatments only tackle the symptoms and do not stop progression of the disease or reverse the neurodegenerative process. While some incidences of Parkinson's disease arise through heritable genetic defects, the cause of the majority of cases remains unknown. Likewise, why some neuronal populations are more susceptible to neurodegeneration than others is not clear, but as the molecular pathways responsible for the process of cell death are unravelled, it is increasingly apparent that disrupted cellular energy metabolism plays a central role. Precise control of cellular calcium concentrations is crucial for maintenance of energy homeostasis. Recently, differential cellular expression of neuronal voltage-gated calcium channel (Ca_V) isoforms has been implicated in the susceptibility of vulnerable neurons to neurodegeneration in Parkinson's disease. Ca_V channels are also involved in the synaptic plasticity response to the denervation that occurs in Parkinson's disease and following chronic treatment with anti-parkinsonian drugs. This review will examine the putative role neuronal Ca_V channels have in the pathogenesis and treatment of Parkinson's disease.

Introduction

Parkinson's disease is a progressive hypokinetic neurodegenerative neurological disorder characterised by bradykinesia, rigidity, akinesia, abnormal posture and resting tremor. In the later stages of the disease autonomic and sensorimotor dysfunction, cognitive decline, depression and sleep disturbances also occur and become clinically relevant (Marsden, 1990). Non-motor functional deficits often precede the major motor symptoms by a number of years and it has been suggested that they are indicative of neurodegeneration that originates in the brain stem and progresses throughout the brain (Braak et al., 2003).

Calcium (Ca²⁺) plays a central role in the normal functioning of neurons and is also involved in the many cellular processes (e.g. oxidative stress, mitochondrial impairment, proteasomal dysfunction, excitotoxicity, neuroinflammation, apoptosis) that can lead to cell death in Parkinson's disease (Berridge et al., 2000, Büeler, 2010, Lau and Tymianski, 2010, Witte et al., 2010, Hegde and Upadhya, 2011). However, it is not clear whether Ca²⁺ dysfunction is causative or secondary to the disease process. Similarly, the reason why some neurons within brain regions degenerate more in affected areas of brain (e.g. ventral–lateral zone > dorsal tier of the substantia nigra (SN)) in Parkinson's disease while other regions containing similar neuron types are less affected (e.g. ventral tegmental area) is unknown. The observation that degenerating neurons in the SN were mainly in areas with low levels of the Ca²⁺ binding protein calbindin-D_28k suggested a role for Ca²⁺ in neuronal susceptibility (Yamada et al., 1990, German et al., 1992, Damier et al., 1999). Another common feature of neurons which degenerate in Parkinson's disease, irrespective of the neurotransmitter type, is that they are poorly myelinated with long fine axons that connect different brain regions (Braak et al., 2004). This, together with the large axonal field of long projection neurons means they have high energy requirements, which necessitates efficient mitochondrial function and a good Ca²⁺ buffering capacity if toxicity through oxidative stress or excitotoxicity is to be avoided (Surmeier et al., 2011).

Recent studies have implicated L-type Ca_V channels (Ca_V1) in the pathogenesis of Parkinson's disease. First, Chan et al. (2007) demonstrated that dopaminergic neurons vulnerable to neurodegeneration in the SN pars compacta of adult (but not juvenile) mice use the Ca_V1.3 subtype of Ca²⁺ channel for pacemaking activity. In contrast, dopaminergic neurons in the adjacent ventral tegmental area, that are less affected by neurodegeneration in Parkinson's disease, rely instead upon sodium ion entry for maintenance of conductance oscillations (Fujimura and Matsuda, 1989, Chan et al., 2007, Khaliq and Bean, 2010). The use of Ca²⁺ rather than sodium ions for pacemaking requires more energy expenditure in order to maintain a safe intracellular Ca²⁺ concentration. This is because extrusion of Ca²⁺ out of the cell and sequestration of Ca²⁺ into intracellular stores requires energy derived from mitochondrial oxidative phosphorylation and the electrochemical gradient for Ca²⁺ across the cellular membranes is much larger (1000×) than that of sodium ions. In Parkinson's disease where mitochondrial dysfunction is evident, the reliance on Ca_V1.3 channels may make the SN pars compacta cells more susceptible to Ca²⁺ mediated excitotoxicity (Chan et al., 2009). The reliance of the SN on Ca_V1.3 channels for pacemaking may also explain the decline in dopaminergic neurons of the SN pars compacta seen with advancing age (Chan et al., 2010). However, Parkinson's disease is not just accelerated ageing because the pattern of cell loss is different in post-mortem brain from non-parkinsonian elderly people to that seen in brain from patients dying with Parkinson's disease (Fearnley & Lees, 1991). Second, retrospective analysis of patients treated with Ca_V1 channel blocking drugs for hypertension and cardiac arrhythmias have indicated a decreased risk for Parkinson's disease in patients treated with dihydropyridines that cross the blood brain barrier, which suggested a neuroprotective effect of such drugs and implied a pathogenic role for the Ca_V1 channel subtype in Parkinson's disease (Becker et al., 2008, Ritz et al., 2010).

This review will examine the role brain Ca_V channels may have in the pathology and treatment of Parkinson's disease. For the above reasons the focus will on the Ca_V1 (L-type current) channel isoforms, but discussion of other subtypes of Ca_V channel will be included when it is pertinent to do so.