Voltage-gated calcium channels and 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-D28k 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 CaV channels (CaV1) 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 CaV1.3 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 CaV1.3 channels may make the SN pars compacta cells more susceptible to Ca2+ mediated excitotoxicity (Chan et al., 2009). The reliance of the SN on CaV1.3 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 CaV1 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 CaV1 channel subtype in Parkinson's disease (Becker et al., 2008, Ritz et al., 2010).
This review will examine the role brain CaV channels may have in the pathology and treatment of Parkinson's disease. For the above reasons the focus will on the CaV1 (L-type current) channel isoforms, but discussion of other subtypes of CaV channel will be included when it is pertinent to do so.
Section snippets
Epidemiology
Parkinson's disease is the most prevalent movement disorder and the second most frequently diagnosed neurodegenerative disease, with an overall incidence in industrialized countries of 0.15–0.3%. The greatest risk factor for Parkinson's disease is increasing age, such that it affects 1% of people over 60 years of age, rising to 2–4% for those aged over 80 (Ben-Shlomo and Sieradzan, 1995, Checkoway and Nelson, 1999, Nussbaum and Ellis, 2003, Leung and Mok, 2005, de Lau and Breteler, 2006). Though
Neuronal voltage-gated calcium channels
The electric potential across cellular membranes is controlled by the gradient of ions produced by membrane pumps, buffering molecules and the activity of the ion channels themselves, either in response to the electrical gradient (voltage sensing ion channels) or inter- and intra-cellular chemical messengers (ligand-gated ion channels) (Aston-Jones & Siggins, 2000). Voltage-gated channels respond to neuronal membrane depolarization by opening and allowing conductance of the ion down the
Pathways to cell death in Parkinson's disease
The pathogenesis of neurodegeneration in Parkinson's disease is multifactorial and theories concerning the origin of cell death processes centre on malfunctioning protein degradation, neuroinflammation and mitochondrial dysfunction occurring because of genetic susceptibility or/and exposure to an environmental toxin (Schapira & Jenner, 2011). The role CaV channels might have in these pathogenic processes is discussed below.
Calcium channel function and Parkinson's disease
The available evidence suggests that CaV1 channels contribute to cell death in Parkinson's disease and that blockade of midbrain CaV1 channels provides some degree of neuroprotection to dying neurons in the SN (Chan et al., 2007, Becker et al., 2008, Ritz et al., 2010). Although in the absence of selective ligands for each Cav isoform, the precise role played by Cav1.2 or Cav1.3 in neurodegeneration or/and neuroprotection cannot be discerned. However, the use of gene knockout models has allowed
Conclusions
The unforeseen connection between Parkinson's disease and CaV1 channel physiology has provided a new avenue of research for understanding the neurodegenerative process that occurs in Parkinson's disease and has also identified CaV1 channels as potential new therapeutic targets for treatment of the disorder.
It will be important to determine whether CaV1 channels function normally in patients with Parkinson's disease. That is, do they contribute to the neurodegenerative process because they are
Conflict of Interest statement
The authors declare that there are no conflicts of interest.
Acknowledgment
No funding source was involved in this work.
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