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Introduction
Voltage-gated calcium channels (VGCCs) are critical determinants of physiological function in both excitable and
non-excitable cells[1,2]. The ability of VGCCs to couple changes in membrane potential to the influx of the pivotal "second
messenger" calcium (Ca2+) bestow VGCCs with a unique and privileged position among ion channels in the coupling of
electrical signaling to intracellular biochemical events. In tissues such as muscle and heart, VGCCs are used for specific
functions such as neurotransmitter release and excitation-contraction coupling, respectively. More generally, VGCCs
orchestrate cell excitability[3], second messenger
signaling[4] and gene
expression[5].
Owing to such diverse roles, it is perhaps not too surprising that disruption in VGCC function has been implicated and,
in many cases, demonstrated to underlie diverse inherited pathologies ranging from cardiac failure to epilepsy. The goal of
this article is to review disparate data on such calcium "channelopathies" from a molecular perspective, focusing on the key
pore-forming alpha subunits.
Structure and function of VGCCs
Although the existence of VGCCs had been known for many decades, their emergence as functionally discrete subtypes
was not revealed until the pioneering electrophysiological studies of
Tsien[6], Lux[7] and many others during the 1980s.
Originally, VGCCs were classified into two groups, according to their functional and pharmacological characteri-stics: T
VGCCs [low voltage-activated (LVA) subtype]; and N, L, P/Q, and R VGCCs [high voltage-activated (HVA)
subtypes][8] (Table 1). However, molecular cloning, expression and biochemical studies revealed inadequacies in the above
classification notation and a more rigorous
structure-based nomenclature (Table 1) was subsequently
introduced[9].
All VGCCs are large (>400 kDa) heteromers comprised minimally of 3 core subunits
a1, a2/d, and b found in a 1:1:1
stoichiometry[8]. Expression studies in
Xenopus oocytes[10,11] and transfected mammalian
cells[12_14] have revealed that the
a1 subunits contain the gating, channel pore and inactivation machinery required for function. However, interactions between
a1 and the auxiliary a2/d and
b subunits are required for optimal cell surface expression and
channel kinetics. Additional protein interactions have been identified that appear necessary for trafficking and regulation (Table 2).
A cardinal feature of VGCCs is their extraordinary propensity for diversity. In mammals, 10
a1, 3 a2/d and 4 b subunit genes have been identified. Moreover, most of the RNA transcripts have been shown to undergo alternative splicing, and
the number of reported variants is growing
rapidly[8]. The precise nature of the
a1, a2/d and b gene products in the VGCC
complexes define their biophysical characteristics, therefore such diversity has significant functional
implications[8]. However, the contribution of any ion channels to integrative physiology also depends on their distribution. Thus, it is
notable that specific VGCCs have unique, but often overlapping, patterns of expression in discrete regions of brain and
other tissues. Even the distribution over the cell surface can
differ[15_22], suggesting that diversity is used to hone
voltage-dependent Ca2+ influx to the demands of discrete functional
compartments[23].
An emerging paradox concerns a subunit, termed
g, first identified as a constituent of the skeletal muscle VGCC but now
known to have relatives in heart and
brain[24]. Precisely what function these
g subunits serve is unresolved. Expression studies suggest an ability to normalize calcium currents to those resembling endogenous
VGCCs[25]. However, not all g subunits show this
effect and one subunit, g2, has been shown to interact with the AMPA-subtype of glutamate
receptors[26].
Ca2+ channelopathies
Inherited defects in VGCCs give rise to some of the most interesting and widely studied
channelopathies[27]. Here we summarize, specifically, current information on those defects arising from mutations in the pore-forming alpha subunits in
human and other model systems (Table 1).
CaV1.1 (a1S) The pore-forming subunit of CaV1.1, encoded in humans by
the CACNA1S (formerly CACNL1A3) gene
on chromosome 1q 31_32[28], is expressed mainly in skeletal muscle traverse tubules where it mediates excitation-contraction
coupling and calcium
homeostatsis[29,30].
Muscular dysgenesis in mice is a lethal mutation derived from a frameshift at nucleotide 4010. The resulting deletion of
the C-terminus leads to a loss in muscle contraction and was the first mutation reported to affect calcium currents
in vivo[31,32]. Missense mutations in CACNA1S have been identified in human cases of hypokalemic periodic paralysis (hypoPP) and
malignant hyperthermia susceptibility
(MHS)[33_38]. The Arg-His or glycine substitutions found in
hypoPP (Table 1) are located in the voltage-sensing segments
(S4) of domains II and IV, leading to a loss of myotube
function[33,39,40]. Arg-His mutations have also been found in patients
suffering from MHS. However, although both allelic, MHS and hypoPP appear to be distinct non-overlapping
diseases[41]. Genetic studies of MHS have mainly linked associated mutations to the ryanodine receptor (RyR). However, as the RyR
comes under the control of CaV1.1 and the R1086H mutation is located in the cytoplasmic loop between transmembrane
spanning segments 3 and 4, such mutations might disrupt the functional link between the CaV1.1 and
RyR[36].
Cav1.2 (a1C) CaV1.2 is primarily localized to cardiac or smooth muscle but is also found in endocrine cells and
neurones. Functionally, CaV1.2 mediates excitation-contraction coupling in smooth and cardiac muscle, hormone secretion
and action potential propagation in sino-atrial and atrio-ventricular
nodes[42].
The CaV1.2 subunit is encoded by the CACNA1C
(formerly CACNL1A1) gene on chromosome
12p13.3[43]. In mice, knockout of the CaV1.2 gene is lethal due to cardiac dysfunction (Seisenberger
et al 2000). However, two de novo missense
mutations in CaV1.2 in humans result in Timothy syndrome, a multi-system disorder including syndactyly, immune deficiency,
long QT syndrome and ventricular arrhythmias during
infancy[44]. These gain of function phenotypes arise from highly
conserved glycine substitutions for either Arg at 406 or Ser at
402[44]. Mutation G406 is located in alternatively spliced exon
8A, at the cytoplasmic face of the transmembrane segment S6 of domain I, whereas mutation G402 is located within the
transmembrane region. As glycine can act as a hinge-point in
a helices, such mutations have been suggested to disrupt the
activation gate[44]. Further support for the role of CaV1.2 in cardiac development and dysfunction comes from studies on
zebrafish whose embryos can survive without blood flow for several days. In their study, Rottbauer
et al[45] mapped the genetic mutations responsible for the zebrafish isl lethal mutant. Mutants expressing two isl nonsense mutations at M379
or M458 (which both caused premature truncation of CaV1.2) present with abnormal heart growth during development.
CaV1.3 (a1D) The pore-forming subunit of the CaV1.1 channel is mainly expressed in endocrine cells of the pituitary
and adrenal chromaffin cells, but is also found in sensory cells and in low densities in atrial muscle, heart and neurons.
Originally classed as the neuroendocrine L-type channel, CaV1.3 plays a role in hormone secretion, mood behaviour, and
control of cardiac rhythm at rest[46].
The CaV1.3 subunit is encoded by the CACNA1D
(formerly CACNL1A2) gene on chromosome
3p14.3[47]. Insights into the role of Cav1.3 in cardiac tissue have largely evolved due to electrophysiology studies on cells from knockout
mice[48] and cardiac cells from human
patients[49]. Although no human gene defect has been reported, animal models have provided
useful insights into potential deficits. In one study, Wappl
et al created a mouse model in which
the high dihydropyridine sensitivity of
Cav1.2 subunits was eliminated by replacement of Thr1066 in helix IIIS5 with a tyrosine
residue[50]. As the distribution of CaV1.2 and 1.3 often overlap, and they both mediate L-type currents, the creation of this mouse model
allowed Sinnegger-Brauns et al, to isolate the function of
Cav1.3 in brain, pancreatic beta cells and the cardiovascular
system[51]. These studies ruled out a direct role for
Cav1.3 in insulin secretion, cardiac inotropy, and arterial smooth muscle
contractility but suggested it might play a role in depression. Although no linkage of CaV1.3 channel mutations has been
reported for human inherited diseases, mice carrying a targeted null allele display profound congenital deafness, thus
providing insight into the molecular basis of Cav1.3 function in auditory
processing[52,53]. Interestingly, the
ise, mutant form of zebra-fish larvae displays a deafness-imbalance phenotype, arising through two mutations (R1250X and R284C) in a gene
encoding for the CaV1.3 channel[54]. The first mutation involves exchange of an Arg codon for a stop codon at position 1250
and results in a nonsense mutation in domain IVS4 that disrupts the transmembrane region and removes the
carboxy-terminal tail. The second mutation substitutes a highly conserved Arg for a Cys residue at position 284 within the
extracellular region of the pore loop between S5 and S6 of domain I.
CaV1.4 (a1F) The CaV1.4 subunit, encoded in humans by the gene
CACNA1F, maps to chromosome
Xp11.4[55] and is mainly expressed in retinal rods and bipolar cells, spinal cord, adrenal gland and mast cells. As its main cellular function is
thought to be neurotransmitter release from photo-receptors, it is no surprize that mutations in this channel are involved
with inherited diseases of the eye.
The locus for X-linked congenital stationary night blindness type 2 (XLCSNB-2) was mapped to the
CACNA1F
gene[55,56] and several mutations have since been identified. In case studies of patients with XLCSNB, over 73
CACNA1F mutations have been detected, of which 51% are nonsense mutations, 32% missense mutations and 8%
frameshifts[57]. A list of several of the mutations identified and their positions within the channel is given in Table 2. Very recently, Wei and
Hemmings detected a genetic association between schizophrenic patients and the
CACNA1F locus, although the exact mutations are
unknown[58]. The prevalence of visual abnormalities in schizophrenia makes an
association with CACNA1F especially interesting.
CaV2.1 (a1A) The P/Q-type calcium channel CaV2.1 (alpha1A) represents one of the most important channels both
from a physiological perspective and its role in channelopathy. Found throughout the nervous system, CaV2.1 is
considered to be the primary VGCC controlling fast neurotransmitter release, especially at excitatory synapses. Not surprisingly,
CaV2.1 is found in high concen-trations in the presynaptic nerve terminus, where it exists in discrete release sites that are
more efficiently coupled to the vesicle release machinery than other
VGCCs[59_62]. However, CaV2.1 is also found
throughout the dendritic arbour, especially in cerebellar Purkinje cells, where it contributes to integrative dendritic
physiology[63].
Historically, one of the first lines of evidence linking
CaV2.1 to neurological disorders came from studies of the tottering
(tg) mouse[64]. The tg mouse is a neurological mutant displaying ataxia, and involuntary spasms indicative of tonic-clonic
seizures as well as neurophysiological signs of absence
epilepsy[65]. The underlying defect in
tg mice has been identified, through positional cloning, as a point mutation (P601L) in
cacna1a, the mouse Cav2.1
gene[64]. Using whole cell patch clamp
methods, Wakamori et al found significant (40%) decreases in P-type
(Ba2+) currents in dissociated Purkinje cells obtained
from tg/tg versus wild-type
(wt) mice that could be replicated in a simple heterologous expression
system[66]. Surprisingly, they found no change in the voltage-dependence of activation or inactivation, single channel conductance or reversal
potential, suggesting that the decreased current density is not due to impaired ion conductance or activation/inactivation
mechanisms.
Three other mouse mutations showing varying degrees of seizure activity have been identified that map to
the cacna1a locus rocker (rkr), tottering leaner
(tgla) and rolling Nagoya
(tgrol) [64,67,68]. Remarkably, each mutant mouse shows
considerable differences in the extent and times of onset of
seizure, cerebellar atrophy and ataxia. Thus
tg, tgla and rkr but not
tgrol mice show seizure activity, whereas
tgla, rkr and
tgrol but not tg mice show marked
ataxia[65,67-69].
Rocker arises through a point mutation within the extracellular
S5_S6 region (T1310K) of domain
III[67]. Surprisingly, the precise effect of the
rkr mutation on P/Q currents has not been forthcoming, but is likely to resemble those in
tg mice. A distinct mutation in domain III, (R1262G), within the
S4 voltage sensor, occurs in
tgrol mice[68]. This mutation displays a marked
reduction in the voltage sensitivity of channel activation. The
tgla mutant has absence seizures, severe ataxia and cerebellar
damage[70]. In tgla, a point mutation at a splice/donor consensus sequence leads to aberrant RNA splicing in the region
encoding the carboxy terminus of the
a1A subunit. As a result, translation yields two primary protein products corresponding
to truncated CaV2.1 subunits bearing a novel and distinct C-termini. Electrophysiological studies on Purkinje cells show that
the major deficit caused by the
tgla mutation is a 60% reduction in P/Q-type currents or current densities compared to the
wild-type mouse[66,71,72]. Single channel recordings suggest the decrease in current densities is not due to effects on either the
channel conductance or lifetimes[72], but due to effects on channel opening probability
(Po) or, more likely, a decrease in channel densities at the cell surface, perhaps due to a trafficking defect. Interestingly, in transfected cells, only the
tglashort form shows a significant reduction in current
density[66].
Just how the phenotypes of these spontaneous mouse mutants arise is unclear but might give insight into the analogous
human conditions[73]. In general, aberrant activity of CaV2.1 channels cannot be functionally compensated for at many
central synapses. Apart from the `gain of function¡¯ FHM mutations (below), impairment of neurotransmission appears to be
the rule for CaV2.1 knockout[74_76],
tg/tg(77) and
tg/tgrol[78,79]
. However, at the climbing fiber-Purkinje cell synapse, evoked
glutamate release is similar between wild-type and
CaV2.1-/-,
tgrol/tgrol or
tg/tg mice[76,78]. Inhibitory transmission does not
appear to be affected[80]. An obvious complication is the degree to which alternate VGCCs can stand in for the aberrant
CaV2.1 channels and to what extent this might contribute to the neurological phenotype. Based on their similar trafficking and
biophysical properties, the most likely replacements are expected to be the
Cav2.2 VGCCs. Indeed, compensation by Cav2.2 has been documented at the calyx of Held synapse in CaV,
CaV2.1-/- knockout mice and other
mutants[74,77,78,81]. However, there is also evidence for upregulation of both CaV2.2 and CaV2.3 at the neuromuscular junction of
CaV2.1-/- mice[82].
In humans, the gene encoding CaV2.1 is designated
as CACNA1A (formerly known as
CACNLA4) and is localized to a large 300 kb region containing 47 exons at chromosome position
19p13[83]. Whereas gene expression yields a primary
transcript of 9.8 kb, several splice variants have been
identified[84], most notably an isoform that differs in exon 37 by 97
nucleotides.
In humans, the cardinal mutation associated with CaV2.1 is a rare disorder termed episodic ataxia type 2 (EA-2) that causes
paroxysmal attacks of cerebellar ataxia that can last for several days. In 1996, Ophoff
et al identified 2 mutations in unrelated patients displaying EA-2 that mapped to
the CACNA1A gene[85]. One mutation involves a base deletion and the other occurs
at a splice junction site, but both are predicted to lead to a frameshift such that the CaV2.1 protein is truncated prematurely
after the S1 region of domain III (Figure 1). The partially complete channel is, thus, predicted to be non-functional or to be
incorrectly folded and trafficked. More recently, additional familial EA-2 mutations have been identified that induce
mis-splicing either through a G-A substitution at an intron-exon boundary or, especially interesting, through a 4 bp ACGT
deletion within an intron (the first described for
CACNA1A), which might unmask a cryptic splice
downstream[86]. Typically, clinical signs of EA-2 are evident prior to adulthood. However, just recently, a case of late-onset (aged 61 years) EA-2 has
been identified involving a 9 bp insertion in the cytoplasmic domain II_III linker. To date this is the largest insertion reported
for the human gene[87]. Quite what the mutation does is unclear. Although it lies within the II_III linker, it is just downstream
of the synprint region for SNAP-25/syntaxin binding. Expression studies indicate a significant (approximately 82%)
reduction in current and a 20 mV depolarization shift in activation threshold with some change in activation and inactivation
kinetics. Together, these data might be indicative of an effect on gating. Why the clinical symptoms appeared so late in this
patient is unclear. An examination of compensatory expression of other VGCCs in this patient would certainly be interesting.
A novel CACNA1A mutation, IVS36-2A>G, at the 3¡¯ acceptor splice site of intron 36 was identified by
sequencing[88]. It is the first described
CACNA1A acceptor splice site mutation and the most C-terminal EA-2-causing mutation reported to date.
Another highly debilitating CACNA1A channelopathy is the rare autosomal dominant disorder familial hemiplegic
migraine (FHM). Characterized by intense attacks of migraine with aura, often lasting for several days, FHM has often been
misdiagnosed as epilepsy or stroke[89]. Cerebellar dysfunction has also been noted in some families. Following the initial
work by Ophoff et al[85], several missense mutations have been found within
CACNA1A that lead to increased calcium influx
through the expressed channels[90]. However, the precise biophysical characteristics conferred by the mutations on the
CaV2.1 channel are not identical. Thus, single channel recordings on expressed channels show changes in gating with
mutants T666M, V714A, and I1819L, but not R192Q. Recovery from inactivation can be slower (T666M) or faster (V714A and
I1819L) compared to wild-type
CaV2.1[91]. Subsequent studies have found an increased propensity for activation at weakly
depolarizing potentials for three additional FHM-associated
mutants[92]. Powerful insights into the neuropathology of FHM
have come from a recent study by Van den
Maagdenberg et al[93] who
generated a transgenic mouse model bearing the
human CACNA1A mutation R192Q. Recordings from cerebellar granule cells showed increased
Cav2.1 channel current densities, which activated at more negative voltages in R192Q mice than wild-type channels. Significantly, the R192Q mice showed
enhanced neurotransmission and susceptibility to cortical spreading depression. Taken together the above suggests that
FHM is a CACNA1A channelopathy that arises through a gain of function that enhances neurotransmitter
release.
As FHM and EA-2 both involve CACNA1A, an interesting question concerns the extent to which they overlap. In this
respect it is notable that approximately 20% of FHM cases show signs of mild cerebellar
ataxia[94]. Although cross-correlational prediction is not straightforward, 83% of patients with six missense mutations associated with migraine also showed
ataxia and or nystagmus[95].
A third clinical disorder associated with mutations in
Cav2.1 has been identified. Termed Spinocerebellar ataxia type 6
(SCA6), this disorder appears in early middle age
(30-40 years) and is characterized by a mild progressive (over a subsequent
25 years) cerebellar atrophy causing dysarthria, nystagmus, ataxia, loss of gait and sometimes
death[96]. Unlike EA-2 and FHM, SCA6 appears to arise through a shift in the reading frame and triplet (CAG) repeat expansion at the distal carboxy
terminus[97]. Based on a study by Ishikawa
et al[98] the critical size of the CAG encoded polyglutamine stretch appears to be
19 repeats, with cases showing longer stretches having poorer neurological outcomes and earlier disease onset. Precisely
what functional effects the SCA6 remains unclear. In a model of SCA6, elongation of the polyglutamine tract in SCA6
CaV2.1 caused a concomitant hyperpolarizing shift of voltage-dependent inactivation to more negative potentials, suggesting an
overall reduction of calcium influx might contribute to SCA6 symptomology. However, just recently, compelling evidence
has been presented that a portion of the CaV2.1 carboxy-terminus is cleaved
in vivo and can enter the nucleus by virtue of
nuclear localization signals[99]. Although the wild-type carboxy terminal fragment is weakly toxic, a fragment containing an
expanded polyglutamine tract (Q33) corresponding to SCA6 is highly toxic to Purkinje neurons and other cells. Thus, SCA6
might share a similar mechanism of action with some other expansion disorders where pathogenesis requires entry of a
polyglutamine-containing fragment into the nucleus.
Given the above, one would anticipate that mutations in the human CaV2.1 gene are associated with
epilepsy[100]. Nevertheless, the evidence has been slow to emerge.
One early study found no statistically significant evidence that genetic
variants of the CACNA1A gene might play a
causative role in common forms of idiopathic generalized epilepsy
(IGE)[101]. Moreover, reports of an allelic association of a silent single nucleotide polymorphism (SNP8) with
IGE[102,103] have been
refuted[104]. Nevertheless, there is growing recognition that in some cases patients with EA-2 also show
an epilepsy phenotype most usually of a primary generalized
nature[105,106].
The first human EA-2-epilepsy case was described in 2001 by
Jouvenceau et al in an 11-year-old who showed frequent
episodes of ataxia and poorly controlled
absence seizures, and generalized tonic_clonic
seizures[105]. The underlying mutation was found to lie in exon 36 (C5733T) giving rise to a premature truncation behind the domain IV S6, and, thus,
complete loss of the C-terminus. In an expression system, the primary effect of this mutation is a massive loss of functional channels
at the cell surface. However, it is interesting to note that the mutation appears to have a
dominant-negative effect when co-expressed with wild-type CaV2.1 (as anticipated for the heterozygous state). It is our contention that it is only a matter of time
before further epilepsy-associated CANA1A mutations are
documented.
CaV2.2 (a1B) Given its established role alongside CaV2.1 in neurotransmitter release, it is remarkable that mutations in
the CACNA1B gene (locus 9q34) have not been identified in the human population. Based on studies in
CaV2.2_/_ knockout mice one would anticipate problems in
nociception[107], decreases in sympathetic nervous system
function[108] and alterations in response to
ethanol[109] and
anaesthetics[110].
CaV2.3 (a1E) The CaV2.3 channel
(CACNA1E) (locus 1q25_q31)[83] is primarily localized to the somata and dendrites of
central neurones. However, such channels are also found in the nerve terminals of central
synapses[111,112] where they might participate in transmitter
release[113]. Although no human mutations have been identified in CaV2.3, observations in knockout
mice by Jing et al predict that mutations impairing this VGCC are likely to affect glucose-stimulated insulin release from
pancreatic beta cells by facilitating the global entry of calcium needed for granule
replenishment[114].
CaV3.1 (a1G) The CaV3.1 subunit gene
CACNA1G, located on chromosome
17q22[115] is thought to encode a T-type (ie
low threshold) VGCC. This channel is highly expressed in brain, especially on dendrites, and it is considered to be the primary
T-channel in the thalamus[116]. However, CaV3.1 is also found in the ovary, placenta and
heart[117] To date no mutations have been identified in inherited human diseases. However, studies on knockout mice indicate reduced sleep
patterns[118,119], bradycardia and delayed atriventricular
conduction[5,120].
CaV3.2 (a1H) In humans, the CaV3.2 gene
(CACNA1H) has been mapped to chromosomal locus
16p13.3[6,121]. This subunit appears to be widely expressed in brain (especially the neocortex), kidney, smooth muscle, liver and heart. Targeted
knockout studies in the rat nociceptive root ganglion suggest CaV3.2 plays a role in
nociception[7,122]. Knockout mice show
constitutively constricted coronary arterioles and focal myocardial
fibrosis[123], and Cav3.1 knockouts in human spermatazoa
demonstrate that CaV3.2 is a key player in the T-type current accompanying the acrosome
reaction[124]. Mutations in CACNA1H
are now thought to underlie diverse epilepsies. Thus, in 2003, Chen
et al found 12 missense mutations in 14 patients with childhood absence
epilepsy[125], and several of the 12 appeared to promote calcium influx during
activation[126]. Even more recently, a study by
Heron et al[127] identified 3 missense mutations and a single nonsense mutation in
CACNA1H in a subset of patients with IGE. On expression, these latter mutations yield statistically significant changes in the kinetics of
activation and inactivation of the CaV3.2 channel. Interestingly, many of these mutations lie in the same domain I_II linker
region. Even more significant is the possibility that mutations in this region might block the selective inhibition of this VGCC
by G-protein b2a2 subunits[128]. Changes in T-type channels have long been implicated in
epilepsy[100].
CaV3.3 (a1I) In humans, the
CACNA1I gene maps to chromosome position
22q12.3 [129]. In common with the other
T-type VGCCs it is expressed highly in
brain[130] where it is thought to play a role in thalamic
oscillation[131]. Little is known about possible CaV3.3 gene defects, either in the human population or inferred from knockout
animals.
Summary
With just a few exceptions, pathological mutations have now been identified in every VGCC pore-forming alpha subunit
in humans. In many cases the pathology can be predicted on the basis of the tissue patterns of gene expression. Studies on
spontaneous mouse mutants provide important clues to the human condition and, in the case of knockout or knockin
mutants, might predict disease phenotype and outcome. What is especially striking is the extent to which small differences
in function can have major and very distinct effects on behavior. Such phenotypic pleiotropy does not simply reflect gain or
loss of VGCC function, but more subtle effects on biophysical parameters such as pore conduction, gating and inactivation
kinetics. In some cases, effects could be attributed to sites of interaction with proteins involved in channel regulation.
However, a largely unexplored area is the extent to which VGCC mutations affect channel trafficking to and from the cell
surface. Just recently, Papazian¡¯s
group[132] identified mutations in
tg/tg mice that appear to disrupt trafficking of CaV2.1 to
the cell surface. Preliminary work in our laboratory suggests that similar effects might occur in other VGCC mutants.
Whatever their origin, it is clear that the list of VGCC mutations identified in the human population will continue to expand.
It is our contention that a detailed understanding of the structural and functional basis of such mutations is essential for
treating the disorders they manifest.
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