COMMUNICATION
Altered Expression and Assembly of N-type Calcium Channel
1B and
Subunits in Epileptic lethargic
(lh/lh) Mouse*
Maureen W.
McEnery
§,
Terry D.
Copeland¶, and
Courtney L.
Vance
From the
Department of Physiology and Biophysics,
Case Western Reserve University, School of Medicine, Cleveland, Ohio
44106-4970 and ¶ ABL-Basic Research Program, NCI-Frederick Cancer
Research and Development Center, National Institutes of Health,
Frederick, Maryland 21702
 |
ABSTRACT |
Voltage-dependent calcium
channels (VDCC) are multisubunit complexes whose expression and
targeting require the assembly of the pore-forming
1 with auxiliary
and
2/
subunits. The developmentally regulated expression and differential
assembly of
isoforms with the
1B subunit to form
N-type VDCC suggested a unique role for the
4 isoform in VDCC
maturation (Vance, C. L., Begg, C. M., Lee, W.-L., Haase, H.,
Copeland, T. D., and McEnery, M. W. (1998) J.
Biol. Chem. 273, 14495-14502). The focus of
this study is the expression and assembly of
1B and
isoforms in the epileptic mouse, lethargic
(lh/lh), a mutant anticipated to produce a truncated
4
subunit (Burgess, D. L., Jones, J. M., Meisler, M. H.,
and Noebels, J. L. (1997) Cell 88, 385-392). In this
report, we demonstrate that neither full-length nor truncated
4
protein is expressed in lh/lh mice. The absence of
4 in
lh/lh mice is associated with decreased expression of
N-type VDCC in forebrain and cerebellum. The most surprising
characteristic of the lh/lh mouse is increased expression
of
1b protein. This result suggests a previously unidentified cellular mechanism wherein expression of the total pool of available
subunits is under tight metabolic regulation. As a consequence of
increased
1b expression, the
1b is increased in its incorporation into
1B/
complexes relative to wild type. Thus, in
striking similarity to the population of N-type VDCC present in
immature rat brain, the population of N-type VDCC present in adult
lh/lh mice is characterized by the absence of
4 with
increased
1b expression and assembly into N-type VDCC. It is
intriguing to speculate that the increased excitability and
susceptibility to seizures observed in the lh/lh
mouse arises from the inappropriate expression of an immature
population of N-type VDCC throughout neuronal development.
 |
INTRODUCTION |
There has been continued effort to determine the molecular origin
of epileptic seizures with the objective of identifying new therapeutic
strategies (1). Recently, attention has been directed to epileptic
strains of animals that exhibit absence seizures with electrographic
firing patterns, onset, localization, and drug response similar to
humans (2). Genetic analysis of the mouse strains tottering
(tg) and leaner (ln) (3, 4) has
identified mutations in the
1A subunit, which, upon
assembly with
and
2/
subunits (5), constitutes
P/Q-type voltage-dependent calcium channels
(VDCC).1 Mutations in the
human
1A gene, however, do not appear to be the locus of
common idiopathic generalized epilepsy (6). It is important to consider
that although mutations in
1 have been demonstrated to
alter the biophysical properties of the VDCC (7), in vitro
recombinant studies have reported modification of VDCC properties that
are a consequence of differential association of
1 with
specific
subunit isoforms (8).
These observations are significant in light of the recent report that
mutation of the
4 subunit is the molecular defect in the epileptic
mouse strain lethargic (lh/lh) (9). The phenotype of homozygous lh/lh mice includes absence seizures,
instability of gait, and convulsions (10, 11). In contrast to the
calcium channelopathies that underlie human spinocerebellar ataxia
(SCA6) (12, 13) and leaner (3, 4), the cerebellum of the
lh/lh mouse is structurally normal (10). Importantly, the
lh gene is anticipated to produce a truncated
4 protein
that does not possess a consensus
1 binding domain that
mediates
1/
interaction (14), suggesting that a
defect in VDCC assembly underlies the pathogenesis of the
lh/lh phenotype.
There is little information available on the mechanisms that regulate
the level of expression of
isoforms and their assembly with
1. Assembly of N-type VDCC subunits has been analyzed in several developing and differentiating systems (15). During IMR32 cell
differentiation,
1b was up-regulated and increased in parallel with
the expression of
1B (16). Expression of
isoforms is
also highly regulated during rat brain ontogeny, with
1b increasing
approximately 3-fold and
4 increasing 10-fold during the interval
between postnatal day 2 (P2) and adult (17). Postnatal assembly of
isoforms with
1B to form N-type VDCC indicated
differential association of
isoforms in immature versus mature forebrain homogenates.
1b was the predominant
detected in
assembled immature N-type VDCC at P2 (17).
4 was not detected as a
component of immature N-type VDCC and was incorporated into mature
N-type VDCC with a time course that paralleled its expression (17).
Thus, differences in the
component of the N-type VDCC defined both
an immature and a mature population of N-type VDCC (17). Although the
significance of
heterogeneity has not been fully explored in
vivo, these developmental studies suggested a unique role of
4
in N-type VDCC maturation. The lh/lh mouse offers the
opportunity to study patterns of
isoform expression that occur in
response to abnormal expression of
4. The focus of this study is the
level of
1B and
subunit expression and assembly of
N-type VDCC in the lh/lh mouse with emphasis upon identifying possible compensatory mechanisms that occur from altered
4 expression.
 |
EXPERIMENTAL PROCEDURES |
Lethargic (B6EiC3H-a/A-lh) and wild-type mice (strain B6EiC3H)
were obtained from Jackson Labs. All reagents were obtained from
sources previously cited (17). Adult mice were euthanized in accordance
with accepted university guidelines, and the brains were removed and
immediately placed in 50 mM Hepes, pH 7.4, 1 mM
EGTA plus protease inhibitor mixture (17). The tissues were homogenized
with a Polytron homogenizer for 10 s and centrifuged at 18,000 rpm
(48,000 × g) for 15 min. The membranes were
resuspended in 50 mM Hepes, pH 7.4, plus protease
inhibitors at a resulting protein concentration of 50 mg/ml. The N-type
VDCC was solubilized from forebrain and cerebellar membranes of
wild-type and lh/lh mice as described previously (18). For
Western blot analysis, all homogenates were stored at
20 °C at
concentrations of 2 mg/ml in sample buffer (5× sample buffer: 325 mM Tris, pH 7.0, glycerol (25% v/v), mercaptoethanol (25%
v/v), SDS (10%)) in 100-µl aliquots. The samples were not
freeze-thawed. The production of anti-peptide polyclonal antibodies to
VDCC subunit epitopes has been described previously (16, 17, 19, 20).
Methods for 125I-CTX binding, Scatchard analysis (21, 22),
quantitative Western blot analysis using 125I-goat
anti-rabbit IgG, immunoprecipitation of N-type VDCC, and all other
general methods have been described in detail (17, 19). The results are
expressed as mean ± S.D. Statistical analysis was performed by a
paired t test or Mann-Whitney Rank Sum test. p
values less than 0.05 were considered significant.
 |
RESULTS AND DISCUSSION |
4 Isoform Is Not Expressed in lh/lh Mice--
The lh
gene mutation was anticipated to lead to truncation of
4 to an
N-terminal fragment predicted to have a mass of 21 kDa (9). The
lh mRNA was detected at levels 20% of the wild-type
4 message (9), suggesting the possibility that the lh
gene product may be expressed in lh/lh mice. Using
4-specific antibodies, we probed forebrain and cerebellar
homogenates from lh/lh mice to evaluate the level of
expression of full-length
4. In contrast to wild-type mice where we
detected full-length
4 (62 kDa), there was no
4 detected in
either forebrain or cerebellum from lh/lh mice (Fig.
1). To further investigate expression of
the lh gene product, we used an antibody (Ab CW24) raised to
amino acids 53-70 in the
4 which are also present in all
isoforms (16, 17). Ab CW24 identified two populations of high (
1b
and
2) and low (
3 and
4) molecular weight
isoforms
previously characterized in rat brain (17). The relative intensity of
these bands clearly differed among the lh/lh
versus wild-type mouse samples (Fig. 1). However, with the
exception of 42-40-kDa proteolytic
fragments, there were no
detectable Ab CW24-immunoreactive proteins that could be attributed to
the predicted 21-kDa product of the lh gene in either
lh/lh mouse forebrain or cerebellum. These results suggest
that the lh mutation causes a complete loss of
4
protein.

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Fig. 1.
4 isoform is not detected in forebrain or
cerebellum of lh/lh mice. Forebrains and cerebella
from lh/lh and wild-type mice were removed, resuspended in
50 mM HEPES, 1 mM EGTA, and protease
inhibitors, and homogenized. The samples (150 µg/lane)
were resolved by SDS-PAGE on a 12% gel (19), transferred to
nitrocellulose, and incubated with affinity-purified antibodies to 4
(1/100 dilution) or Ab CW24 (a pan-specific anti- antibody, 1/200
dilution) and visualized with enhanced chemiluminescence. Lane
1, lh/lh cerebellum; lane 2, wild-type
cerebellum; lane 3, lh/lh forebrain; lane
4, wild-type forebrain.
|
|
The Pool of Available
Subunits Is Decreased in lh/lh
Mice--
To investigate the pool of available
isoforms in
forebrain and cerebellum of lh/lh and wild-type samples, the
level of expression of all
isoforms was quantified using a
pan-specific anti-
antibody (Ab CW24) and a panel of
isoform-specific antibodies. There are regional differences in
expression of
isoforms with increased expression of all
isoforms (with the exception of the
4) in forebrain samples.
Significantly, we observed differences in expression among specific
isoforms in lh/lh mice compared with wild-type mice. The
level of expression of all
isoforms as detected by the anti-
pan-specific antibody is lower in lh/lh forebrain and cerebellum than in wild-type samples (Fig.
2), indicating that the level of total
isoforms is not maintained in the lh/lh samples. In both
lh/lh forebrain (p < 0.001) and cerebellum
(p < 0.05), the level of expression of
1b was
increased compared with wild-type mice (Fig. 2). In forebrain, the
increase in
1b expression was greater than 50%. These results are
consistent with our previous characterization of
1b as an inducible
and regulated protein (16, 17). In contrast, differences in the levels
of expression of
2 and
3 in lh/lh versus
wild-type mice were not statistically significant in either forebrain
or cerebellar samples.

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Fig. 2.
Altered level of expression of isoforms
in wild-type and lh/lh brain. Forebrains
(FB) and cerebella (CB) from lh/lh and
wild-type mice were removed, resuspended in 50 mM HEPES, 1 mM EGTA, and protease inhibitors and homogenized. The
samples (150 µg/lane) were resolved by SDS-PAGE,
transferred to nitrocellulose, and incubated with affinity-purified
antibodies pan-specific for all and isoform-specific antibodies to
1b, 2, 3, and 4. The amount of was quantified using
125I-IgG. Results obtained were from duplicate blots
representing n = 3 wild-type ( ) and 3 lh/lh ( ) animals for forebrain samples and
n = 2 wild-type and 3 lh/lh animals for
cerebellar samples; **, p < 0.001 and *,
p < 0.05 as determined by a paired t
test.
|
|
Decreased Expression of N-type VDCC and
1B in lh/lh
Compared with Wild-type Mice--
The density of N-type VDCC has been
previously shown to be higher in forebrain versus cerebellar
samples (21, 23, 24). Furthermore,
4 is the predominant isoform
associated with VDCC from cerebellum, and
3 is the predominant
isoform associated with VDCC from forebrain (5, 17, 20, 25). Therefore, these patterns of VDCC subunit expression suggested regional
differences in acquisition of functional N-type VDCC in cerebellum and
forebrain from lh/lh versus wild-type mice. Using
125I-CTX radioligand binding assays and Scatchard analyses
(18) (Fig. 3), we observed a significant
decrease (p < 0.05) in expression of N-type VDCC in
lh/lh forebrain (1.49 ± 0.41 pmol/mg) compared with
wild-type forebrain (2.70 ± 0.63 pmol/mg). There was a single 125I-CTX binding site detected in the forebrain samples
with Kd values of approximately 28 pM
for both the lh/lh and wild-type samples. The level of
1B expressed in forebrain samples was also quantified
(Fig. 3) to examine possible discrepancies between expression of
125I-CTX binding sites and
1B protein (17).
Despite the decrease in 125I-CTX binding sites in
lh/lh forebrain, similar levels of
1B protein
are expressed in forebrain of lh/lh and wild-type mice. These data strongly suggest that expression of
1B
protein in forebrains of lh/lh mice is maintained at
wild-type levels, while the assembly of
1B into a
complex that can support 125I-CTX binding is compromised.
The decreased expression of 125I-CTX binding sites in
lh/lh forebrain (Fig. 3) may reflect the decreased
availability of
(Fig. 2) required to traffic
1B to the plasma membrane (26).

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Fig. 3.
Differential expression of 1B
and N-type VDCC in wild-type and lh/lh mouse
brain. Forebrains (FB) and cerebella (CB)
from lh/lh and wild-type mice were removed, resuspended in
50 mM HEPES, 1 mM EGTA, and protease
inhibitors, and homogenized. The samples (150 µg/lane)
were resolved by SDS-PAGE, transferred to nitrocellulose, and incubated
with affinity-purified antibodies to 1B subunit (Ab
CW14). The amount of 1B was quantified using
125I-IgG. The results obtained were from duplicate blots
representing n = 3 wild-type ( ) and 3 lh/lh ( ) mice for forebrain samples and n = 2 wild-type and 3 lh/lh mice for cerebellar samples; **,
p < 0.001, as determined by a paired t
test. Scatchard plot analysis of 125I-CTX binding to N-type
VDCC in wild-type and lh/lh mouse forebrain and cerebellum
was carried out as described (17, 18). The amount of protein per assay
was: lh/lh forebrain, 3-5 µg; wild-type forebrain, 2-4
µg; lh/lh cerebellum, 11-20 µg; and wild-type
cerebellum, 9-20 µg. The following Kd values were
calculated: lh/lh forebrain, 27.8 (± 7.6) pM;
wild-type forebrain, 28.4 (± 15.3) pM; lh/lh
cerebellum, 75.6 (± 10.0) pM; and wild-type cerebellum,
66.6 (± 5.0) pM. The results obtained were from tissue
samples representing n = 4 wild-type and 3 lh/lh animals for forebrain samples and n = 3 wild-type and 3 lh/lh animals for cerebellar samples; *,
p < 0.05, as determined by a paired t
test.
|
|
We also observed decreased expression (p < 0.05) of
125I-CTX binding sites in lh/lh cerebellum
(0.32 ± 0.05 pmol/mg) compared with wild-type cerebellum
(0.53 ± 0.10 pmol/mg). However, in contrast to the forebrain
samples, radioligand binding experiments detected two
125I-CTX binding sites in cerebellum. The high affinity
site (Kd values of approximately 70 and 67 pM for the lh/lh and wild-type cerebellar
samples, respectively) is characteristic of the N-type VDCC. The low
affinity site for 125I-CTX detected in cerebellar samples
is likely because of the low affinity binding of 125I-CTX
for the P/Q-type VDCC (5) and was not pursued further in these studies.
In contrast to lh/lh forebrain, decreased
1B protein is expressed in lh/lh mouse cerebellum, suggesting
that expression of
1B protein is not maintained at
wild-type levels. It seems reasonable to consider that the loss of the
4 from lh/lh cerebellum cannot be entirely compensated
despite the increased level of expression of
1b (Fig. 2). The
decreased expression of N-type VDCC or altered expression of other VDCC
in the cerebellum of the lh/lh mouse may be the molecular
basis of ataxia associated with the lh/lh phenotype. It
should be stated that the level of expression of functional N-type VDCC
in sympathetic neurons was also decreased in "
3 knock-out mice"
(27). However, in contrast to the lh/lh mouse, the "
3
knock-out" mouse is phenotypically normal (27). The expression of
other
isoforms in response to the elimination of
3 has not yet
been reported.
Increased Incorporation of
1b into N-type VDCC of the lh/lh
Mouse--
To determine the structural consequences of abnormal
isoform expression in lh/lh mice upon N-type VDCC assembly,
the endogenous
1B/
subunit complexes were evaluated
in immunoprecipitation assays using anti-
1B, anti-
generic (Ab CW24), and
isoform-specific antibodies (17). The assay
conditions were defined such that the pan-specific anti-
antibody
immunoprecipitated a similar fraction of N-type VDCC in all samples
(Fig. 4). The relative contribution of
isoforms to the N-type VDCC present in forebrain and cerebellum of
lh/lh is clearly altered compared with the wild-type mice
(Fig. 4). As anticipated from the lack of detectable
4 in forebrains
from lh/lh mice (Fig. 1), the disparity in the association of
4 with N-type VDCC in lh/lh versus
wild-type mice was quite dramatic, as antibodies to
4
immunoprecipitated less than 10% of the total N-type VDCC solubilized
from the cerebellum of lh/lh mouse (Fig. 4). With regard to
the N-type VDCC extracted from forebrain, the fraction of N-type VDCC
associated with
1b was statistically increased in lh/lh
versus wild type mice (Fig. 4). In contrast, neither the
association of
2 nor
3 with the N-type VDCC was affected in
forebrains of lh/lh versus wild-type mice (Fig.
4). However, although
1b was increased in expression in lh/lh cerebellum (Fig. 2), there was no statistically
significant increase in incorporation of any
isoform into
cerebellar N-type VDCC (Fig. 4). It is reasonable to suggest that
down-regulation of
1B expression (Fig. 3), rather than
increased incorporation of
1b into assembled N-type VDCC, is the
primary mechanism of compensation in lh/lh cerebellum.
Additional studies are required to determine whether the compensatory
mechanisms that alter
subunit composition of the N-type VDCC in the
lh/lh mouse influence the expression and assembly of other
VDCC.

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Fig. 4.
Altered 1B/ subunit
assembly leads to different populations of N-type VDCC in
wild-type and lh/lh brain. Forebrains
(FB) and cerebella (CB) from lh/lh
( ) and wild-type ( ) mice were solubilized with 0.75% CHAPS
incubated with 125I-CTX (9000-12,000 cpm/assay) for 30 min. Affinity-purified antibodies to the 1B (Ab CW14),
pan-specific anti- antibodies, and isoform-specific antibodies to
1b, 2, 3, and 4 (25 µg/assay) were added for 1 h
(17). Protein A-Sepharose 4B was added with constant mixing.
125I-CTX bound to the immunoprecipitated N-type VDCC was
recovered in protein A pellets, counted, and normalized to the fraction
of 125I-CTX immunoprecipitated by Ab CW14 (17, 19). The
approximate amount of total 125I-CTX binding/sample prior
to immunoprecipitation was in the range of 1000-1600 specific
counts/min of 125I-CTX for the cerebellar samples and
2500-8000 specific counts/min of 125I-CTX for the
forebrain samples. Results obtained were from n = 4 wild-type and 4 lh/lh animals carried out in duplicate; *,
p < 0.05 and **, p < 0.001 as
determined by a paired t test.
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|
Although the specific biophysical properties derived from the
population of N-type VDCC present in wild-type and lh/lh
forebrain have yet to be determined, it is interesting to note that
1b and
4 have similar effects upon closed state inactivation of recombinant N-type VDCC (8). Similar kinetic effects of
1b and
4
suggest tolerance of the
1b assembled into N-type VDCC, and this
atypical channel composition may explain the absence of the
neurodegeneration frequently observed in other epileptic mouse strains
(3, 4).
These results are the first to indicate that assembly of the high
voltage-activated N-type VDCC is altered in the lh/lh mouse. These findings do not exclude the possibility that the expression of
other high voltage-activated VDCC is also effected as
4 is associated with mature L-type, N-type, and P/Q-type VDCC (17, 20, 25).
However, it is interesting to point out that although low
voltage-activated T-type channels have been implicated in the
initiation of thalamic seizures in absence epilepsies (28, 29), the
T-type
1G and
1H isoforms do not contain
consensus
binding domains (14, 30), suggesting that T-type VDCC
expression, unlike the high voltage-activated VDCC, may not be directly
regulated by
subunits.
Differential modulation of the N-type VDCC by protein kinases in
lh/lh mice is another property that may result from the
assembly of
1b in place of
4. The
1b (31) contains consensus
sites for protein kinase A modification; conversely in the
4, the
protein kinase A consensus sites are absent (32). Thus, the
inappropriate inclusion of
1b into the N-type VDCC complex in the
lh/lh mouse in lieu of
4 may alter protein
kinase-mediated modulation of the channel and thus effect calcium entry
and calcium-dependent signaling.
Subunit Composition of N-type VDCC Expressed in lh/lh Mice
Resembles N-type VDCC Population of Immature (P2) Neurons--
In
earlier studies,
4 was discriminated from the other
isoforms by
virtue of its striking increase in expression during development (17,
33). The importance of
4 to neuronal functioning is reflected in the
epileptic and ataxic phenotype of the lh/lh mice, which
stands in contrast to the "
3 knock-out" mouse that is
phenotypically normal (27). The phenotype of lh/lh mice is evident at postnatal day 15 (10, 11), which is consistent with the loss
of
4 that is normally increased in expression after P7 in developing
rat brain (17). The question now arises as to whether the phenotype of
lh/lh mice arises primarily because of the loss of
4 or
as a result of the increased fractional contribution of
1b to N-type
VDCC complexes. Our recent report that identifies
4 as a marker for
N-type VDCC maturation unifies these two possibilities (17). The
increased fractional contribution of
1b to N-type VDCC complexes and
the absence of
4 assembled into adult lh/lh N-type VDCC
result in a population of N-type VDCC that is strikingly similar to
immature (P2) N-type VDCC in
subunit composition (17). We
propose that the mechanism that promotes absence seizures in
lh/lh mice, a form of epilepsy more commonly associated with immature brain (28), may be a consequence of prolonged and
inappropriate expression of immature
1/
complexes.
 |
ACKNOWLEDGEMENTS |
We thank Stefan J. Dubel for technical
assistance and preparation of the figures for publication. We also
thank Dr. Ben Strowbridge, Dr. J. P. Jin, Dr. Richard Zigmond, and Dr.
Stephen Jones for critical discussion of the manuscript.
 |
FOOTNOTES |
*
This study was funded in part by the National Institute of
Mental Health (to M. W. M.), Life and Health Insurance Medical Research Fund (to M. W. M.), American Heart Association (to
M. W. M.), and in part by the National Cancer Institute, Department
of Health and Human Services, under contract with ABL (to T. D. C.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
§
Established Investigator of the American Heart Association. To whom
correspondence and reprint requests should be addressed: Dept. of
Physiology and Biophysics, Case Western Reserve University, School of
Medicine, 10900 Euclid Ave., Cleveland, OH 44106-4970. Fax:
216-368-1693; E-mail: mwm4{at}po.cwru.edu.
The abbreviations used are:
VDCC, voltage-dependent calcium channel; N-type VDCC,
-conotoxin-sensitive VDCC;
1B, 230-kDa subunit of the
N-type VDCC
2/
, 160-kDa subunit of N-type VDCC
1-
4, 53-85-kDa subunits of N-type VDCC125I-CTX, 125I-labeled Tyr-22-
-conotoxin GVIACHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonatePAGE, polyacrylamide gel electrophoresisP2, postnatal day 2.
 |
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