A Lethal Convergence of Dopamine and Calcium
D. James Surmeier1,*
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
The controversy about whether dopamine contributes to cell loss in Parkinson’s disease takes a new turn
as Mosharov et al. in this issue of Neuron demonstrate that Ca2+influx through L-type channels elevates
dopamine synthesis to potentially toxic levels in vulnerable ventral mesencephalon neurons.
Parkinson’s disease (PD) afflicts millions.
It is the second most common neurode-
generative disease, robbing sufferers of
many capacities, including the ability to
risk factor for PD, which means that as
improvements in health care drive up the
average life span, the number of people
suffering from PD will increase. Projec-
tions are that the number of Americans
suffering from PD will double by 2025
(Dorsey et al., 2007).
To make matters worse, nothing is
known to slow the inexorable progression
of the disease. In large measure, this is
because we don’t know what causes it.
The paper by Mosharov et al. (2009) in
this issue of Neuron appears to provide
The cardinal symptoms of PD—rigidity,
tremor, bradykinesia—result from the
death of a small group of dopaminergic
the substantia nigra pars compacta (SNc;
Hornykiewicz, 1966; Riederer and Wuke-
tich, 1976). We know this in part because
boosting the production of dopamine by
(L-DOPA) does a good job of ameliorating
symptoms, at least in the early stages of
The question Mosharov and colleagues
(2009) asked was why SNc dopaminergic
neurons were vulnerable. Dopamine itself
has long been suspected to be a culprit
in PD. Dopamine catabolism or oxidation
wreaking all sorts of havoc inside cells
(Burke et al., 2004; Eisenhofer et al.,
2004; Greenamyre and Hastings, 2004).
But there are problems with this model.
One is that not all dopamine neurons in
the brain die in PD (e.g., Damier et al.,
1999; Saper et al., 1991). As a matter of
fact, neighboring dopaminergic neurons
in the ventral tegmental area (VTA) are
largely spared in PD. So, while the use of
dopamine as a transmitter was potentially
dangerous, it alone couldn’t explain
Mosharov et al. (2009) reasoned that
maybe it was the quantity of dopamine,
not the quality. But how to measure dopa-
mine where it really matters, in the cyto-
plasm? By using an innovative combina-
tion of patch clamp and amperiometric
approaches, Mosharov et al. (2009) were
able to measure cytosolic dopamine
concentrations in living neurons, albeit
exposing them to L-DOPA. After carefully
characterizing how cytosolic dopamine
vesicular sequestration, and catabolism,
Mosharov et al. (2009) made a key
discovery—cytosolic DA concentrations
in vulnerable SNc DA neurons were 2- to
3-fold higher than in resistant VTA DA
neurons, rendering them much more
sensitive to the toxic effects of an acute
L-DOPA challenge. This difference was
mine storage or dopamine degradation,
leaving differences in synthesis as the
most likely culprit.
The study doesn’t provide a definitive
answer but does provide a tantalizing
clue. Cytoplasmic Ca2+concentrations
are higher in SNc dopaminergic neurons
than neighboring VTA neurons because
they use L-type Ca2+channels to help
maintain autonomous pacemaking (Chan
et al., 2007). When these channels are
antagonized or cytoplasmic Ca2+extrinsi-
cially buffered, the differences in cytosolic
dopamine went away—arguing that Ca2+
was boosting dopamine synthesis. More
importantly, antagonizing L-type Ca2+
channels significantly diminished the toxic
effects of L-DOPA. This model fits nicely
with the early observation that expression
of calbindin, a Ca2+buffering protein, is
negatively correlated with vulnerability in
PD (Damier et al., 1999; German et al.,
1992). Mosharov et al. (2009) also show
that alpha-synuclein (a major component
of Lewy bodies associated with PD)
factors into this equation, perhaps by
being converted into an inhibitor of chap-
erone mediated autophagy by dopamine
So, are SNc dopaminergic neurons
particularly vulnerable in PD not because
they make dopamine per se, but because
they make too much? The ability of L-type
Ca2+channel antagonists to diminish the
sensitivity of SNc dopaminergic neurons
to toxins used to create animal models of
PD is certainly consistent with this idea
(Chan et al., 2007), as is the diminished
risk of developing PD with the use of
Ca2+channel antagonists to treat hyper-
tension (Becker et al., 2008). But it should
be remembered that Ca2+itself poses
a challenge to cellular longevity (Mattson,
2007; Nicholls, 2009). Sustained Ca2+
influx, like that seen in pacemaking SNc
problem for mitochondria which have
long held center stage in thinking about
the etiology of PD (Schapira, 2008). Not
only are they largely responsible for
producing the adenosine triphosphate
(ATP) necessary to keep intracellular
Ca2+concentrations within acceptable
limits, they directly participate in Ca2+
buffering (Nicholls, 2009). Because aging
diminishes the mitochondrial capacity
to generate ATP through oxidative phos-
phorylation, neurons with a Ca2+reliant
Neuron 62, April 30, 2009 ª2009 Elsevier Inc.
should be operating nearer
and nearer their peak meta-
bolic capacity, diminishing
episodic challenges (Nicholls,
(Sulzer, 2007; Figure 1).
As fascinating and plau-
sible as this story is, a 300
pound gorilla is sitting in the
corner. Is PD really a dopami-
nergic disorder? To be sure,
loss of SNc dopaminergic
neurons is responsible for
the motor symptoms of the
disease, but there are a host
of nonmotor symptoms that
have their origins elsewhere
and colleagues (2004) have
argued that the Lewy body
pathology characteristic of
in the non-dopaminergic neurons of the
dorsal motor nucleus of the vagus.
Regardless of whether you are convinced
of the caudal-to-rostral staging in PD
proposed by Braak (Burke et al., 2008;
Lees, 2009), there is no arguing with the
distributed LB pathology and loss of
non-dopaminergic neurons in PD. What
makes these neurons vulnerable is unre-
solved, but the work by Mosharov et al.
(2009) elegantly drives home the lesson
that figuring this out is likely to come
from understanding how cellular risk
factors converge to determine vulnera-
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Figure 1. Calcium Enhancement of Dopamine Synthesis Leads to
Increased Stress in Substantia Nigra Dopaminergic Neurons
Neuron 62, April 30, 2009 ª2009 Elsevier Inc.