M O D U L A T O R
alomone labs
Headquarters: Alomone Labs Ltd. Har Hotzvim Hi-Tech Park P.O. Box 4287, Jerusalem 91042, Israel.
Tel: +972-2-587 2202 Fax: +972-2-587 1101 or +972-2-642 6975 email: [email protected]
Ion Channels in Cancer
[email protected]
http://www.alomone.com
Noemí Bronstein-Sitton, Ph.D.
Are Ion Channels the Next Frontier in Cancer Research?
Introduction
Ion channels have long been known to be involved in the regulation of a
variety of biological functions ranging from the control of cell excitability
to the regulation of cell volume and proliferation. Because of the
ubiquitous presence of ion channels in virtually all cells and their critical
involvement in diverse biological functions, it came as no surprise when
several human and animal diseases were attributed to defects in ion
channel function. Indeed, the term channelopathies was coined to
describe the ever growing number of diseases associated with ion
channel function. Channelopathies have been recognized in the context
of conditions as diverse as epilepsy1, cardiac arrhythmias2, skeletal
muscle disorders3 and diabetes4.
Lately, increasing evidence suggests that yet another disease can be
ascribed, at least in part, to ion channel malfunction: cancer. Although we
are still a long way from cataloguing cancer as a channelopathy, that is,
a disorder arising directly from ion channel dysfunction, there is mounting
evidence pointing to the involvement of ion channels in cancer
progression and pathology. In this review we will summarize the latest
findings concerning the involvement of ion channels in cancer.
The Making of a Cancer Cell
Before considering ion channel involvement in
tumor development, a brief discussion of how
cancer evolves at the cellular level seems
appropriate in order to better understand
the context of ion channel participation in
this process.
The development of cancer in humans is a
multistep process that usually occurs over many
decades. This process involves the alteration of
genes and/or proteins involved in cell
proliferation, apoptosis and differentiation.
Therefore, in the first step, a cancer cell acquires
a phenotype that either allows it to proliferate
without limits, evade apoptosis, generate its own
mitogenic signals or ignore growth-inhibitory
ones (see Figure 1).
At a later stage the cell would need to attract
vasculature (angiogenesis) so as to sustain the
increasing number of cancer cells. Still later, the
cell would need to acquire a phenotype that
allows it to invade and colonize (metastasize)
neighboring or even distant tissue.
It is generally accepted that the disruption of a
relatively small number of genes or proteins with
key roles in the above mentioned pathways is
essential for the development of the neoplastic
phenotype. Indeed, a mutated version of the
ras protein that is constitutively active and
therefore signals continuous mitogenic stimuli,
has been identified in about a quarter of human
tumors.5 Similarly, the p53 tumor-suppressor
protein which controls DNA repair and apoptosis
pathways is mutated in nearly half of human
tumors.6
This is not to say that only mutations in these
particular proteins can induce neoplastic
transformation, but rather that they are
key regulators of their specific pathway.
For example, overexpression of the tyrosine
kinase receptor HER2/neu, which is an upstream
regulator of ras, occurs in a large percentage of
breast cancers.7
While the biochemical pathways involving ras
–mediated mitogenic stimulation or p53 directed
apoptosis are relatively well understood,
the molecular circuitry enabling enhanced
secretion of angiogenic factors from cancer cells
is largely unknown. Similarly, the regulation of
the elements controlling the migration and
extravastion capabilities of cancer cells is poorly
understood.
The Involvement of Ion Channels in the Neoplastic Phenotype
The contributions of ion channels to the
neoplastic phenotype are as diverse as the ion
channel families themselves and therefore a
comprehensive review of all the channels and
their possible functions in cancer progression is
beyond the scope of this review. A brief
examination of the known (and possible)
contribution of ion channels to the biology of
the cancer cell will be discussed below. The
largest number of studies are concerned with
the involvement of ion channels in cell cycle
regulation. Ion channels control cell proliferation
Ion Channels in Cancer
in several ways. First, ion channels (mainly
voltage-gated K + channels) control the
maintenance of the membrane potential and
changes in membrane potential are absolutely
required throughout the cell cycle. The other
way by which ion channels are involved in cell
cycle progression is by controlling cell volume.
Cell proliferation must, at some point, lead to
cell “swelling”, a closely regulated process that
includes activity of K+ and Cl channels.26 Not
surprisingly, the same ion channel mechanisms
that regulate cell proliferation are involved in
the control of the other side of the coin:
apoptosis. Cell shrinkage is one of the early
events marking the onset of apoptotic cell
death. Again, a prominent role for K+ and Clchannels has been established in this process,
although the molecular identity of the Cl channels has not been determined.27 Cytosolic
Ca 2+ increase plays a key role in both
proliferation and apoptosis, although the nature
of the Ca2+-permeable channels involved and
their regulation remains obscure. 2 6 , 2 7
The potential role of ion channels in tumor-
MODULATOR Issue No.17 Spring 2003
1
M O D U L A T O R
alomone labs
induced angiogenesis has not been properly
addressed until now. In this process, tumor cells
secrete proangiogenic factors such as vascular
endothelial growth factor (VEGF), basic
fibroblast growth factor (bFGF) and others,
which stimulate endothelial cells to form blood
vessels.28 Several classes of ion channels are
expressed on endothelial cells although their
functional role has only begun to be
investigated.29
Invasive growth or cell migration is a highly
regulated process in which the migrating cells
must secrete matrix proteases that disrupt the
extracellular matrix (ECM) and permit easier
transit through the surrounding environment.
In addition, they must also profoundly reshape
their structure, which involves massive
cytoskeletal rearrangement. There is increasing
Figure 1
From Normal Cell to Tumor in 3 Basic Steps
Step 1: keep proliferating
normal cells
A mutation occurs
that allows cells to
keep proliferating or
avoid apoptosis.
GF
Growth
Factor
Receptor
Cellular stres:
DNA damage, Nitric
Oxide, hypoxia, etc.
p53
Adaptor
Protein
gene transcription
RAS
Raf
cell apoptosis DNA
cycle
repair
arrest
MAPK
cell proliferation
Step 2: angiogenesis
Normal and
mutated
cells
The growing number of
proliferating cells need to
attract blood vessels
(angiogenesis) in order to
receive nutrients, O2, etc.
to sustain themselves.
Ion Channels in Cancer
information concerning ion channel involvement
in cytoskeleton reshaping and cell-cell
interaction 30 and also some evidence that
tumor cell invasion can be halted by the use
of channel blockers (see below). A revision
of the accumulated data on the involvement
of at least some of the ion channel families
in neoplastic transformation will be presented
below.
A. Voltage-Gated K + Channels
The most compelling evidence
concerning the involvement
o f ion cha nn els in t he
transformation process is
related to the overexpression
of voltage-gated K+ channels
in a variety of cancers.
Voltage–gated K+ channels is a
surprisingly large (about 40
human genes have been
identified until now) and
ubiquitously expressed protein
family. All members of the
family consist of a pore-forming
unit (also called α subunit) with
six transmembrane spanning
segments that selectively
conduct K+ ions across the cell
membrane. A typical voltagegated channel is composed of
f ou r α sub un it s (e it he r
homomeric or heteromeric) and
four (optional) auxiliary β
subunits, which have regulatory
functions. The voltage-gated K+
channel family can be further
divided in 4 subfamilies based
Step 3: colonize other tissues
The transformed cells are able
to enter the blood stream
(and survive there) and colonize
(metastasize) other tissues.
on amino acid similarity and some functional
properties. They are the Kv (Shaker-like), the
ether-a-go-go (EAG), the KCNQ and the BK
(Ca 2+ -activated K + channels) subfamilies.
As their name implies, voltage-gated K +
channels open in response to a depolarization of
the cell membrane, thus allowing an efflux of K+
ions. Channels that belong to the BK subfamily
in addition to being voltage-sensitive, can also
open in response to an increase in intracellular
Ca 2+ . 8 - 9 Voltage-gated K + channels are
ubiquitously expressed and are the main
channels responsible for maintaining membrane
potential in diverse cells. There is a strong
correlation between membrane potential and cell
proliferation: terminally differentiated cells (that
do not proliferate) are very hyperpolarized, while
cycling cells (such as tumor cells) are very
depolarized. 10 It has been suggested that
activation of K+ channels is necessary for the
progression of the cells through the G1 phase of
the cell cycle. Indeed, inhibition of these
channels by pharmacological agents has been
shown to inhibit cell proliferation in both normal
activated lymphocytes and various cancer
cell lines.10
For the most part however, the identity of the
specific channel involved in cell cycle regulation
in the different cell types has not been clearly
established. On the other hand, mounting
evidence has identified channels of the eag
subfamily as highly involved in the development
of cancers of both hematopoietic and nonhematopoietic origin. The eag subfamily of
voltage-gated K+ channels can be subdivided
into three distinct groups based on sequence
homology. They are the eag, the eag-like K+
channels (elk) and the eag-related genes
(erg).11In the last few years, a growing number of
studies have shown that a member of the erg
family, the erg1 gene (also known as human
erg1 or HERG1), is selectively upregulated in a
MODULATOR Issue No.17 Spring 2003
2
M O D U L A T O R
alomone labs
variety of human and animal tumors while its
expression is absent in the normal tissue or cell
line counterparts.12-15 (see Figure 2) Moreover,
selective pharmacological blockage of the HERG
channel in several primary leukemic cells
significantly reduced cell proliferation.14,15 It is still
unclear, however, how over-expression of this
particular voltage-dependent K + channel
contributes to the neoplastic phenotype.
One possibility is that the special properties of
HERG channels contribute to maintain a more
depolarized membrane potential and thus permit
an easier passage through the cell cycle. In a
recent report, it was shown that the oncogene
v-src (a constitutively active form of the protein
tyrosine kinase src) could phosphorylate the
HERG channel and thus induce an increased
current.16 Since aberrant function of proteins in
the ras-src signaling pathway is a common
feature of transformed cells as discussed above,
src-mediated modulation could be a mechanism
that regulates HERG function in cancer cells.
Another study showed that the
HERG channel expressed in cell
lines and primary tumors was
preferentially a heterotetramer
formed by the “regular” herg1 gene
transcript and an alternative splice
variant termed herg1b.
The biophysical properties of the
resulting channel turned out to be
quite different than those exhibited
by HERG in normal cells.
In addition, the expression of the
two HERG protein isoforms was
strongly cell cycle-dependent. 17
Another study demonstrated that
HERG protein physically interacted
with the tumor necrosis factor
receptor type 1 (TNFR1) in the cell membrane of
tumor cell lines.18 TNFR1 is the ubiquitously
expressed receptor for the TNFα cytokine that
can mediate both cell proliferation and apoptosis
in many cells.19 The significance of its interaction
with the HERG channel however, is not clear.
Another group within the eag-K + channel
subfamily that has been clearly implicated in
malignant transformation is the eag group itself.
In this group two genes have been identified:
eag1 and eag2. The expression of both proteins
is largely restricted to the brain, however several
groups found evidence indicating that eag1 was
inappropriately expressed in several cancer cell
lines.20-22 Moreover, one study showed that EAG1
by itself had oncogenic potential as a cell line
transfected with the channel induced aggressive
and faster tumor growth in vivo as compared to a
cell line transfected with an unrelated Kv
channel.22
The same study also showed that inhibition of
eag1 expression with antisense oligonucleotides
was sufficient to decrease the proliferation of
various cancer cell lines. As is the case for the
HERG1 protein, the contribution of EAG1
to tumor development is believed to be
related to its ability to modulate cell cycle
progression.
Another voltage-dependent K+ channel subfamily
that can be involved in tumor progression is the
BKCa subfamily. This subfamily is also known as
2+
Ca -dependent K + channels meaning,
as mentioned above, that they allow K+ efflux in
response to an increase in intracellular Ca2+.
BKCa channel over- expression was identified
in primary human gliomas, which showed
a positive correlation between BKCa channel
expression levels and tumor malignancy. 23
Another study showed that specific BKCa channel
blockers could inhibit cell proliferation in
an astrocytoma cell line.24 Although the number
of reports linking BKCa expression and/or function
to cancer development is not large at the
moment, it could be worthy to further explore
Figure 2
HERG protein detection in leukemic cell line FLG 29.1 Cells
were immunostained with an Anti-HERG primary antibody (#APC-062)
directed against the C-terminus of HERG (magnification was 20X).
The image was kindly contributed by Serena Pillozzi and Annarosa
Arcangeli. Department of Experimental Pathology and Oncology,
University of Firenze, Italy.
this topic.
As a K + channel sensitive to
intracellular Ca 2+ levels, BK Ca
channels sit at the crossroads of
several metabolic pathways
including cell proliferation,
apoptosis, and cell migration.
Indeed, the BK Ca channel has
been shown to be a physiological
target of the ras protein in
fibroblast cell lines. In these cells,
BKCa channel blockers were able
to inhibit mitogen-induced cell
proliferation indicating that BKCa
is an essential member of
the ras-controlled proliferation
pathway.25
B. Miscellaneous Ion Channels
An assorted collection of ion channels has been
implicated in cancer progression. In most cases, there
are only preliminary reports showing an aberrant
expression of a particular ion channel in cancer
malignancies whereas the biological implications
of their abnormal expression are not clear.
TRPV6 (also known as CaT1 and CaT-L) is a
member of the TRP superfamily of non-voltagegated cation channels. TRPV6 is a Ca2+ selective
channel that is believed to be involved in Ca2+
Ion Channels in Cancer
reabsorption by epithelial kidney and gut cells.
TRPV6 was demonstrated to be abundantly
expressed in prostate tumors but not in healthy
prostate tissue. 31 Moreover, its expression
was enhanced in a variety of human tumors of
epithelial origin.32
Another channel that may be involved in tumor
progression is P2X7. This channel is an ATP-gated
cation channel (permeable to both Ca2+ and Na+),
which is widely expressed in immune cells.
Opening of P2X7 channels by extracellular ATP
induces a wide range of biological responses,
including cell proliferation, apoptosis, modulation
of cytokine secretion, etc. Indeed, it has been
shown that P2X7 expression is enhanced in a
form of B-cell leukemia.33
Finally, the voltage-gated L-type Ca2+ channel
(Cav1.2 or α1c) was significantly increased in
colon cancer epithelial cells when compared with
adjacent normal tissue.34
MODULATOR Issue No.17 Spring 2003
3
M O D U L A T O R
alomone labs
Final Considerations
In the next few years we will probably see an
expansion of the increasing list of ion channels
implicated in cancer development as the
awareness and the tools needed to investigate
this issue are more readily available.
As is the case with other protein families, it will
be probably difficult to ascribe tumor
development to the malfunction of a single ion
channel. Rather, defects in ion channels
probably contribute to the neoplastic phenotype
through complex interactions with other
proteins, most of which have not been properly
identified. Along the same line, there is
increasing evidence that ion channel
investigation will become an integral part of
fields ranging from cell-cell adhesion,
arteriosclerosis and immune dysfunction.
Since in many cases there are already known
pharmacological modulators (blockers and
activators) of ion channels, identification of a
single defective ion channel in a particular
cancer could provide a ready-to-go therapeutic
approach.
The opposite can also be true. As the
chlorotoxin story beautifully demonstrates, a
well-known toxin against a non-identified ion
channel can become a potent anti-cancer drug
(see below for more details).
In synthesis, in the next few years we are
poised to see new and exciting discoveries
regarding ion channels and their function in
cancer development.
R e f e r e n c e s
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Kaneko, S. et al. (2002) Neurosci. Res. 44, 11.
Marban, E. et al. (2002) Nature 415, 213.
Jurkat-Rott, K. et al. (2002) J. Neurol. 249, 1493.
Nichols, C.G. et al. (2002) Am. J. Physiol. Endocrinol.
Metab. 283, E403.
McCormick, F. (1991) Environ. Health Perspect. 93, 17.
Hahn, W.C. et al. (2002) N. Engl. J. Med. 347, 1593.
Wang, S.C. et al. (2001) Semin. Oncol. 28, 115.
Yellen, G. (2002) Nature 419, 35.
Shieh, C. et al. (2000) Pharmacol. Rev. 52, 557.
Wonderling, W.F. et al. (1996) J. Membrane Biol. 154, 91.
Bauer, C.K. et al. (2001) J. Membrane Biol. 182, 1.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
Bianchi, L. et al. (1998) Cancer Res. 58, 815.
Cherubini, A. et al. (2000) Br. J. Cancer. 83, 1722.
Garth, A. et al. (2002) J. Biol. Chem. 277, 18528.
Pillozzi, S. et al. (2002) Leukemia. 16, 1791.
Cayabyab, F. S. et al. (2002) J. Biol. Chem. 277, 13673.
Crociani, O. et al. (2003) J. Biol. Chem. 278, 2947.
Wang, H. et al. (2002) Cancer Res. 62, 4843.
Wallach, D. et al. (1999) Annu. Rev. Immunol. 17, 331.
Meyer. R. et al. (1998) J. Physiol. 508, 49.
Meyer. R. et al. (1999) J. Membrane Biol. 171, 107.
Pardo, L.A. et al. (1999) EMBO J. 18, 5540.
Liu, X. et al. (2002) J. Neurosci. 22, 1840.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
Basrai, D. et al. (2002) Neuroreport. 13, 403.
Huang, Y. et al. (1994) J. Biol. Bhem. 269, 31183.
Lang, F. et al. (2000) Cell. Physiol. Biochem. 10, 417.
Yu, S.P. et al. (2001)
Tossetti, F. et al. (2002) FASEB J. 16, 2.
Nilius, B. et al. (2001) Physiol. Rev. 81, 1415.
Schwab, A. et al.
(2001) Am. J. Physiol. Renal Physiol. 280, F739.
Wissenbach, U. et al. (2001) J. Biol. Chem. 276, 19461.
Zhuang, L. et al. (2002) Lab. Invest. 82, 1755.
Adinolfi, E. et al. (2002) Blood, 99, 706.
Wang, XT. et al. (2000) Am. J. Pathol. 157, 1549.
Correspondence to: Noemí Bronstein-Sitton, Ph.D. Email: [email protected]
The Chlorotoxin Story:
Cutting Edge Anti-Cancer Drug.
Chlorotoxin is a 36-amino acid peptide that
was originally isolated from the venom of the
Leiurus quinquestriatus scorpion as a putative
Cl channel inhibitor.1 It was later found that
Chlorotoxin could inhibit invasiveness of
glioma cells in vitro. This inhibition was
attributed to the ability of Chlorotoxin to block
an unidentified Cl channel that was putatively
involved in the process of regulatory volume
decrease, a key step in cell migration. 2
Interestingly, Chlorotoxin was found to bind
specifically to glioma cell lines and primary
cultures, but not to normal brain cells.
This aspect, together with the proven ability of
Chlorotoxin to inhibit glioma cell migration,
placed this molecule as an attractive
candidate for the treatment of glioma
malignancies.3 Indeed, the FDA has recently
granted approval for a phase I/II clinical trial
Ion Channels in Cancer
From Cl - Channel Inhibitor to
Noemí Bronstein-Sitton, Ph.D.
using an iodinated Chlorotoxin derivate
( 131 I-Chlorotoxin) for the treatment of brain
tumors. Lately, it has been shown that contrary
to the original hypothesis, the specific
Chlorotoxin target in the surface of glioma cells
is the matrix metalloproteinase-2 (MMP-2)
protein and not a Cl channel. 4 MMP-2 is a
member of a protein family involved in the
proteolytic degradation of cell surface and
extracellular matrix (ECM) proteins and
therefore implicated in the regulation of cell
proliferation, differentiation and migration.
Metalloproteinases (MPs) have long been
recognized as potential targets for the
development of anticancer drugs for use in a
variety of tumors. 5 Until now however, the
attempts to develop MP inhibitors have proven
ineffective. Chlorotoxin, as a specific MMP2
inihbitor, could then become a useful drug for
the treatment of cancer and a range of other
diseases. Further research will be needed to
establish how binding to MMP2 is connected to
the previously reported function of Chlorotoxin
as a Cl channel inhibitor.
We have recently made available, a highly
pure, biologically active, recombinant
Chlorotoxin (rChlorotoxin; #RTC-450).
For more information please refer to the List of
Products, table- “Cl - Channel Blocker”.
R e f e r e n c e s
1.
2.
3.
4.
5.
DeBin, J.A. et al. (1991) Toxicon 29, 1403.
Soroceanu, L. et al. (1999) J. Neurosci. 19, 5942.
Soroceanu, L. et al. (1998) Cancer Res. 58, 4871.
Deshane, J. et al. (2003) J. Biol. Chem. 278, 4135.
Baker, A.H. et al. (2002) J. Cell Sci. 115, 3719.
MODULATOR Issue No.17 Spring 2003
4
M O D U L A T O R
alomone labs
Related Products
Ion Channel Modulators
Ordering
Information
Technical Information
Compound
M.W.
Purity
( )-Bay K 8644
rBeKm-1
356.3
4098
6979
Activate L-type; 1µM
>99%
>98% Specifically blocks ERG1 K+ channel with IC50 of
3.3 nM.
>98%
Neuronal L-type blocker; 1-10nM.
7036
>98%
Mesobuthus eupeus
Calcicludine
Specific Channel Modulation Activity
and Effective Concentrations
rBeKm-1
Cat. #
B-350
RTB-470
Control
C-650
Dendroaspis angusticeps
Calciseptine
L-type blocker; 100nM - 2µM.
C-500
Dendroaspis p. polylepis
rCharybdotoxin
Leiurus q. hebraeus
rChlorotoxin
Leiurus q. hebraeus
E - 4031
rErgtoxin-1
>99% High (BK) or intermediate (IK1) conductance Ca2+
-activated and voltage-gated (Kv1.3) blocker;
10 - 100nM.
3996 >99% Blocks at sub-micromolar concentration small
conductance Cl- channel of epithelial cells & also
blocks Cl- channels expressed in gliomas.
500nM - 5µM.
510.48 >98% Voltage-gated (HERG) blocker;100 nM - 1µM
4738 >98%
ERG K+ channel blocker; IC50=16nM.
4353
50nM rBekm-1
RTC-325
RTC-450
E-500
RTE-450
Centruroides noxius
7004
>98%
L-type blocker; 100nM - 2µM.
F-700
4231
>99%
RTI-400
Isopimaric Acid
302
>99%
rNoxiustoxin
4195
>99%
302
85-90%
High conductance Ca2+-activated K+
channel (BK) blocker; 50 - 100nM.
BK Channel Opener
1 - 50µM.
Some Ca2+-activated and voltage-gated
K+ channel blocker; 10 - 100nM.
BK Channel Opener
1 - 50µM.
L-type blocker; 50 - 500nM
FS-2
The effect of 50nM rBeKm1 on hERG1 channels
expressed in Xenopus oocytes. Responses to 200
ms pulses from holding potential of -100mV
to + 20mV, before and during application of
50nM rBeKm1, with 2mM K+ as charge carrier.
Dendroaspis p. polylepis
rIberiotoxin
Buthus tamulus
Centruroides noxius
Pimaric Acid
(PiMA)
TaiCatoxin
52,000 >97%
I-370
RTN-340
P-270
T-800
Oxyuranus s. scuttelatus
For price and ordering information please refer to the List of Products.
Calcicludine
The effect of 500nM
calcicludine on heterologously
expressed L-type calcium
currents (CaV1.2/ α2δ1/ β2a,
RNA injected into Xenopus
oocytes).
A
B
Legend
Control
Calcicludine
0
A: I-V relation before (circle)
and during (triangles), bath
perfusion of the toxin.
-0.2
B: An example of current
response to 200 ms
depolarization to +20 mV
(from holding potential of
–100 mV) before (red) and
during (black) perfusion of
the toxin.
Ion Channels in Cancer
-0.4
-40
-20
0
20
Voltage
40
60
80
MODULATOR Issue No.17 Spring 2003
5
M O D U L A T O R
Related Products
alomone labs
( )-Bay
The effect of 5µM
( )-Bay K 8644 on heterologously
expressed L-type calcium
currents (CaV1.2/ α2δ1/ β2a, RNA
injected to Xenopus oocytes).
A
Legend
Control
( )-Bay K 8644
-0.2
A: I-V relation before
(circle) and during
(triangles), bath perfusion
of the compound.
K 8644
B
0
B: An example of current
response to 200 ms
depolarization to +20 mV
(from holding potential
of –100 mV) before (red)
and during (black) perfusion
of the drug.
-0.1
-40
0
-20
20
40
60
80
Voltage
rErgtoxin-1
A
A. hERG channels currents recorded
from Xenopus oocytes (in 5mM K+)
elicited by 500ms depolarization
from holding potential of –100mV
to +20mV, before and during
application of rErgtoxin-1 at the
indicated concentration.
B
1.2
1
Control
10 nM
50 nM
100 nM
B. Mean ± S.D, dose response for
rErgtoxin-1 block of hERG channels
(n was between 2-7 oocytes for
each point).
0.8
0.6
0.4
0.2
0
1
10
100
1000
[rErgtoxin-1] (nM)
Related Antibodies
Ordering
Information
Technical Information
Description
Application
Family
Reactivity
Confirmed
WB, IH
rat, mouse,
rabbit, human
rat, mouse
Anti-CaV1.2α1C
(L-type)
Anti-BKCa
WB, IH
Voltage-Gated
Ca2+ Channels
K+ Channels
Anti-erg1
WB, IH
K+ Channels
rat, human,
Anti-HERG
WB
K+ Channels
human
Anti-EAG2
WB
K+ Channels
rat
Anti-P2X7
WB, IH
Purinergic
Receptors
rat, mouse
Epitope
Cat. #
Epitope location
Peptide corresponding to
residues 848-865 of rat CaV1.2 (α1C).
GST fusion protein corresponding to
residues 1098-1196 of mouse Slo (mSlo).
Peptide corresponding to
residues 1122-1137 of rat erg1.
GST fusion protein corresponding to
residues 1106-1159 of human erg (HERG).
Peptide corresponding to
residues 842-860 of rat EAG-2.
Peptide corresponding to
residues 576-595 of rat P2X7.
Intracellular loop between II
and III domains.
Intracellular, C-terminus.
ACC-003
Intracellular, C-terminus.
APC-016
Intracellular,
near the C-terminus.
Intracellular, C-terminal.
APC-062
APC-053
Intracellular, C-terminus.
APR-004
APC-021
For price and ordering information please refer to the List of Products, tables.
Ion Channels in Cancer
MODULATOR Issue No.17 Spring 2003
6
Related Products
alomone labs
1
1
2
2
1
205
205
116
Western blotting of
rat brain membranes:
1. Anti-α1C antibody
(#ACC-003) (1:200).
2. Anti-α1C antibody,
preincubated with the
control peptide antigen.
M O D U L A T O R
117
96
66
45
2
97
Western blotting of the lysate
of HEK 293 cells, stably expressing
HERG channels (the line generously
provided by Dr. Craig T. January,
University of Wisconsin):
1. Anti-erg1 antibody
(#APC-016) (1:200).
2. Anti-erg1 antibody, preincubated
with a control peptide antigen.
66
45
32
20
Western blotting
of rat brain
membranes:
1. Anti-P2X7 antibody
(#APR-004) (1:1000).
2.Anti-P2X7 antibody,
preincubated with a
control peptide.
Staining of the interpeduncular
nucleus (IPN) with Anti-BKCa antibody
(#APC-021) green fluorescence.
Ventromedial substantia
nigra, pars compacta (VMSNC)
Contributed by Shai Shoham Ph.D.
Herzog Hospital, Jerusalem.
1
IPN
2
205
148
60
42
30
Ion Channels in Cancer
Western blotting of rat
brain membranes:
1. Anti-BKCa antibody
(#APC-021) (1:300)
2. Anti- BKCa antibody,
preincubated with the
control antigen.
MODULATOR Issue No.17 Spring 2003
7