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J Biol Chem, Vol. 274, Issue 29, 20123-20126, July 16, 1999
From the Departments of The activation of T-lymphocytes is dependent
upon, and accompanied by, an increase in voltage-gated
K+ conductance. Kv1.3, a Shaker family
K+ channel protein, appears to play an essential role in
the activation of peripheral human T cells. Although Kv1.3-mediated
K+ currents increase markedly during the activation process
in mice, and to a lesser degree in humans, Kv1.3 mRNA levels in
these organisms do not, indicating post-transcriptional regulation. In
other tissues Shaker K+ channel proteins
physically associate with cytoplasmic Voltage-gated K+ channels play an important role
in the propagation of electrical signals in the nervous system of
higher organisms (1). A large number of voltage-gated K+
channel proteins are expressed throughout the mammalian nervous system.
These proteins are encoded by a large number of genes which fall into
various families or subfamilies of homology. The mammalian
Shaker family of K+ channels contains at least
seven different genes, Kv1.1-Kv1.7 (2), which form functional homo-
and heterotetrameric channel complexes (3, 4). Furthermore, it has been
shown that in the mammalian nervous system the channel-forming
Shaker proteins are usually complexed with cytoplasmic Kv Coexpression studies, utilizing mRNA injection and voltage-clamp
analysis of Xenopus oocytes, have shown that the major brain Kv In addition to their role in the nervous system, K+ channel
proteins are expressed in other cell types, where they may help determine membrane potential and maintain osmotic equilibrium. What
specific physiological roles might these K+ channel
proteins play outside the nervous system? They appear to play an
essential role in the stimulation and maintenance of cellular
proliferation of T cells (11), B cells (12), macrophages (13), and
brown adipocytes (14). In T-lymphocytes, the role has been extensively
investigated: mitogens cause an immediate shift in K+
conductance (15, 16); activated T cells show substantially greater
K+ conductances than quiescent cells (11, 17); activation
is attenuated by membrane depolarization (18); and pharmacological agents that inhibit K+ channel conductances block T-cell
proliferation (19). In human peripheral T-lymphocytes, the Kv1.3
K+ channel plays a critical role in mediating the
K+ current increase, which accompanies proliferation (20),
and is also likely to be the site of blockade, which inhibits this event (21). Interestingly, Kv1.3 mRNA does not appear to be up-regulated during proliferation, indicating that the Kv1.3 gene product is post-transcriptionally regulated (22, 23).
Recent studies have shown that Kv In Vitro Transcription and Oocyte Injection--
The
Kv Microinjection and Electrophysiology--
Ovaries of specimens
of Xenopus laevis were surgically removed, and individual
oocytes were dissected away in a saline solution (ND96) containing 96 mM NaCl, 2 mM KCl, 1.8 mM
CaCl2, 2 mM MgCl2, and 5 mM HEPES at pH 7.4 with NaOH. Stage V and VI oocytes were treated for 2 h with collagenase (1 mg/ml) in
Ca2+-free ND96 to discard follicle cells. cRNA solutions of
50 nl were injected into oocytes using the Nanoject injector apparatus (Drummond Scientific, Broomall, PA). Measurement of ionic currents in
Xenopus oocytes was performed using standard two-electrode voltage clamp techniques. Recordings were obtained with the
GeneClamp500 voltage clamp and the PCLAMP software package (Axon
Instruments, Foster City, CA). Electrodes of 0.4-1.0 megohms were
filled with 1 M KCl. Recordings were conducted in ND96
solution. Data were leak subtracted using hyperpolarizing P/4
subtraction pulses from a holding potential of Cell Culture--
Peripheral blood mononuclear cells were
isolated by Ficoll Gradient and then added to media containing 10%
fetal calf serum, 100 units/ml penicillin, 100 mg/ml streptomycin, and
100 units/ml interleukin-2. One-half of the cells were frozen at
Western Blot Analysis--
Human T-lymphocytes were treated with
or without phytohemagglutinin as described above. These cells were then
homogenized in RIPA buffer (25 mM Tris, pH 7.4, 150 mM KCl, 5 mM EDTA, 1% Nonidet P-40, 0.5%
sodium deoxycholate, and 0.1% SDS). Proteins were size-fractionated on
a 9% SDS-polyacrylamide gel and then transferred to Nitrocellulose
membrane. The membranes were blocked in 100 mM
phosphate-buffered saline containing 10% nonfat dried milk and 0.05%
Tween-20. The anti-Kv Kv1.3 Expression--
Representative current traces of uninjected
oocytes (Fig. 1A) and oocytes
injected with 0.2 ng of Kv1.3 cRNA (Fig. 1B) are shown. The
time course of Kv1.3 expression in the absence of
For all of the experiments reported below, Kv1.3 RNA was injected into
Xenopus oocytes at concentrations, approximately 0.2 ng/oocyte, which produced relatively small currents. At concentrations as much as 10-fold higher, the relationship between the amount of RNA
injected and current amplitudes is linear, suggesting that cellular
translation and transport functions are not saturated in this
concentration range (Fig. 1 D).
Functional Expression of
Xenopus oocytes were injected with Kv1.3 cRNA and saturating
amounts of Kv Functional Expression of Kv T-lymphocytes are critical for eliciting cellular immune
responses. It is well established that K+ channels play
important roles in the activation of T-lymphocytes: important
physiologic changes which T-lymphocytes undergo as a result of the
activation process are inhibited by blockers of K+
channels, including protein synthesis, cell volume increase, and
cell-cycle progression (17, 19).
It has been demonstrated that channels containing the Kv1.3 subunit are
the major K+ channel (type n channel) in
T-lymphocytes (25). The K+ conductance increases 20-fold in
murine T-cells treated with mitogen, whereas in human T-cells, the
K+ conductance increases roughly 2-fold (11, 17). However,
treatment of these cells by a mitogen results in constant or decreased, rather than increased, Kv1.3 mRNA levels in mice and humans,
respectively (22, 23). On the other hand, it has been shown that the
expression of the murine Kv Our results show that Kv1.3 can form functional channels alone but that
the presence of Kv We thank Herman Moreno for critical review of
the manuscript.
*
This work was supported by National Institutes of Health
Grants NS30989 and NS35215 (to B. R.).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.
§
To whom correspondence should be addressed: University of Arizona,
Dept. of Molecular and Cellular Biology, Life Sciences South 552, Tucson, AZ 85721-0106. E-mail: yando@geocities.com.
The Effects of Shaker 
-Subunits on the Human
Lymphocyte K+ Channel Kv1.3*
§,,
,, and
Physiology and Neuroscience
and of Pathology, New York University, School of Medicine,
New York, New York 10016 and ¶ Ventana Genetics,
Salt Lake City, Utah 84108
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
-subunits (Kv1-3).
Recently it has been shown that Kv1 and Kv2 are expressed in
mouse T cells and that they are up-regulated during mitogen-stimulated activation. In this study, we show that the human Kv subunits substantially increase K+ current amplitudes when
coexpressed with their Kv1.3 counterpart, and that unlike in mouse,
protein levels of human Kv2 remain constant upon activation.
Differences in Kv2 expression between mice and humans may explain
the differential K+ conductance increases which accompany
T-cell proliferation in these organisms.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
subunits (Kv1-Kv3) (5).
subunit (6), Kv2, and at least one splice form of Kv1 (Kv1a) are able to alter the inactivation properties of a number of
neuronally expressed Kv1 channel proteins (7, 8). In contrast, neither
of these two Kv subunits significantly alters the inactivation
properties of Kv1.3, a K+ channel that is sparingly
expressed within the nervous system (9). Perhaps more importantly,
Kv subunits are also able to increase K+ current
amplitudes of neuronal Kv1 K+ channels in the oocyte plasma
membrane (8). Furthermore, coexpression of several neuronal Kv1
channels with Kv2 in mammalian cell lines has shown that Kv2
increases the number of these Kv1 proteins reaching the membrane
surface (10). Taken together, these studies indicate that the Kv
subunits are likely to increase the surface expression of
functional, neuronal K+ channels.
2, and Kv1 to a lesser extent,
are both expressed in mouse T-lymphocytes (24). Moreover, the murine
Kv mRNA and protein levels are markedly increased upon
interleukin-2 stimulation. If the Kv subunits were able to increase
the surface expression of Kv1.3 channels, then up-regulation of Kv
subunits would result in greater K+ channel surface
expression and therefore greater K+ conductance during the
proliferation of T-lymphocytes and perhaps other cell types (11-14)
The extent of Kv subunit up-regulation in response to T-cell
activation could therefore account for the extent to which
Kv1.3-mediated K+ current is elevated in different
organisms. Utilizing the Xenopus oocyte expression system,
we report the effects of coexpression of the human Kv1a and Kv2
subunits on the expressed current levels of Kv1.3 channels.
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
1 and Kv2 cDNAs were subcloned into a vector containing 40 adenosine residues downstream of the 3' cloning site and linearized
with NotI. The 1 cDNA had 10 nucleotides 3' of the stop codon. The human Kv1.3 gene was transcribed from linearized template. For more efficient expression in oocytes (8), the 5'
untranslated sequences immediately upstream of the ATG start codon of
Kv2 and Kv1.3 were changed to CGCCGCCAAG. Oocytes were injected with
50 nl of cRNA at varying dilutions. All electrophysiology experiments
were carried out at approximately 20 °C.
80 mV. The interpulse
interval was 25 s. K+ conductances were calculated
using a reversal potential of 80 mV.
80 °C immediately after separation and thawed into media. The
other cells were activated with phytohemagglutinin at 5 µg/ml at
37 °C. Cells were activated for 72 h.
2 polyclonal antibody (Quality Controlled
Biochemicals, Inc., Hopkinton, MA) raised against the C-terminal 18 amino acids of the Kv2 protein was recognized by an anti-rabbit IgG
secondary antibody. Membranes were washed in 100 mM
phosphate-buffered saline containing 3% dried milk and 0.05%
Tween-20. Immunoreactivity was visualized by a horseradish peroxidase-catalyzed color reaction (Pierce, Rockford, IL).
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
-subunits was
observed. Recordings at +60 mV were taken at 18, 24, 36, 48, and
72 h after injection. Kv1.3 channels expressed a slowly
inactivating current (
= 548 ms at +60 mV ± 38 ms,
n = 8). The current amplitude of Kv1.3 continued to
increase with increasing time, with levels still increasing up to
72 h after injection (Fig. 1C).
View larger version (10K):
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Fig. 1.
Kv1.3 K+
currents. Shown is the family of K+ currents
representing uninjected oocytes (A) and oocytes injected
with 0.2 ng of Kv1.3 cRNA (B). Currents were elicited by 2-s
pulses from 60 to +60 mV in 10-mV increments, from a holding
potential of 80 mV. Current amplitudes of Kv1.3 at +60 mV as a
function of time after injection are plotted in panel C. The
relationship between the amount of Kv1.3 cRNA injected and the current
amplitudes expressed at +60 mV at 48 h after injection are plotted
in panel D (n = 8). Data are mean
values ± S.E.
1.32,K+ Channel
Complexes--
To investigate the potential effects of the
-subunits on Kv1.3 current, we first co-injected Kv1.3 with varying
amounts of Kv2 cRNA. We observed that the enhancement of Kv1.3
expression increased markedly until the 2 cRNA level approached
10-fold that of the Kv1.3 cRNA (Fig.
2A). Beyond that ratio, there
was little increase in the enhancement of current, suggesting that saturating amounts of the Kv2 subunit had been reached.
View larger version (28K):
[in a new window]
Fig. 2.
Effects of Kv
subunits on Kv1.3 current amplitudes. A, oocytes
were coinjected with 0.2 ng of Kv1.3 and 0, 0.02, 0.2, 2, 4, or 6 ng of
Kv2 cRNA. 24 h after injection, the oocytes were depolarized to
+60 mV from a holding potential of 80 mV. Peak currents at each
concentration were averaged (n = 12 for each
concentration). B, Xenopus oocytes were injected
with 0.2 ng of Kv1.3 alone, or with 4 ng of Kv2 or 4 ng Kv1a cRNA
and voltage-clamped (600-ms pulses to +60 mV from a holding potential
of 80 mV) 18, 24, 48, and 72 h later. Currents for each
condition were averaged (n = 10) and normalized to the
peak values obtained with oocytes injected with Kv1.3 alone at each
time point. The data represent mean values. Left bar, 1.3;
middle bar, 1.3 + Beta1; right bar, 1.3 + Beta2.
2 cRNA. Recordings were taken at 18, 24, 48, and 72 h after injection. At all time points investigated, there was a
striking increase in the current amplitude of Kv1.3 when co-expressed with Kv2 (Fig. 2B). The increase in current of Kv1.3 in
the presence of saturating amounts of Kv2 was 4-fold (±0.38,
n > 10) at 18 h, 4.2-fold (±0.45,
n > 10) at 24 h, 3.2-fold (±0.38,
n > 10) at 48 h, and 2.6-fold (±0.44,
n > 10) at 72 h (Fig. 2B). Marked increases in current were obtained when at least equal amounts of Kv1.3
and Kv2 cRNA were used. Unlike Kv1.4, the inactivation of Kv1.3 was
not accelerated when coexpressed with Kv2 (Fig. 3, A and C). Scaled
currents of Kv1.3 alone (Fig.
4A) and Kv1.3 with Kv2
(Fig. 4B) show that kinetics of Kv1.3 are not significantly altered by the presence of Kv2. Plots of the normalized
voltage-conductance relationships (Fig.
5) rule out the possibility that the
Kv-mediated increases in current amplitude are because of
alterations in the voltage-gating properties of Kv1.3 channels; the
probability of opening is saturated at approximately +20 mV both in the
absence and presence of the Kv subunits.
View larger version (20K):
[in a new window]
Fig. 3.
Kv1.3 current properties in the presence of
Kv subunits. Shown is the family of
K+ currents elicited by 2-s pulses from 60 to +60 mV in
10-mV increments from a holding potential of 80 mV, 48 h after
injection. A, Kv1.3 alone (.2 ng); B, Kv1.3 and
Kv1a (0.2 and 4 ng); C, Kv1.3 and Kv2 (0.2 and 4 ng).
The time scale is indicated by the horizontal bar for all
traces while current amplitudes are indicated by the vertical
bar.
View larger version (28K):
[in a new window]
Fig. 4.
Kv 2 does not affect
Kv1.3 current kinetics. Shown is the family of K+
currents elicited by 2-s pulses from 60 to +60 mV in 10-mV increments
from a holding potential of 80 mV, 48 h after injection.
Currents elicited by Kv1.3 alone (A) and Kv1.3 with
saturating amounts of Kv2 cRNA (B). Current amplitudes
are scaled to equal heights. The horizontal bar indicates
time scale for all traces.
View larger version (11K):
[in a new window]
Fig. 5.
Voltage-dependence of Kv1.3 with and
without -subunits. Conductance voltage
relationships were determined by depolarizing from a holding potential
of 80 to pulses ranging from 60 to +60 mV in 10-mV increments from
Xenopus oocytes 24 h after injection. Conductance
values were normalized to the maximum conductance, and the mean
values ± S.E. were plotted against the depolarizing potential.
Kv1.3 (circles), Kv1.3 with Kv1 (triangles),
and Kv1.3 with Kv2 (squares).
1.31,K+ Channel
Complexes--
We coinjected Xenopus oocytes with Kv1.3
cRNA and saturating amounts of Kv1 cRNA. Unlike most other Kv1
channels, Kv1.3 did not exhibit rapid inactivation when co-expressed
with Kv1 (Fig. 3B), though controls performed with Kv1.4
and Kv1 confirmed that the 1 cRNA was being translated properly
(data not shown). We observed an increase in current amplitude when
Kv1.3 was co-expressed with Kv1, peaking at slightly more than
2-fold at 24 h, but by 72 h after injection the Kv1.3 current
amplitude in the presence of Kv1 decreased to 67% of the current of
Kv1.3 injected alone (Fig. 2B). The voltage-dependence of
Kv1.3 was not affected by the presence of the Kv1 subunit (Fig. 5).
Taken together, the data indicate that although the Kv subunits do
not alter gating or inactivation, they strongly regulate the expression
of functional channels at the cell surface membrane.
2 Subunit Protein Expression--
A polyclonal antibody
against Kv2 was used to detect the expression of -subunits in
T-lymphocytes. In both quiescent and activated T-lymphocytes, a 39-kDa
protein is detected at levels which remain relatively constant (Fig.
6). This 39-kDa protein is identical in
size to the Kv2 channel subunit purified from bovine brain (6) and
the Kv2 subunit detected in activated murine T-lymphocytes (24). A
faint band just below the 39-kDa band in Fig. 6 is likely to correspond
to a previously reported splice variant of Kv2 (GenBank accession
number 2827466), in which 14 amino acids near the N terminus of the
protein are absent. In contrast to murine T-lymphocytes, the expression
levels of Kv2 do not change in activated human T-cells.
View larger version (61K):
[in a new window]
Fig. 6.
Western blot analysis of
Kv 2 protein expression in quiescent and
activated human T-lymphocytes. Cell extracts were analyzed for
Kv2 protein levels by Western blot analysis. Lane 1,
unstimulated human T-cells; lane 2, T-cells stimulated
for 72 h with phytohemagglutinin (5 µg/ml). 100 µg of protein
were added to both lanes.
DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
2 subunit increases markedly in response
to stimulation by interleukin-2 (24).
subunits, primarily Kv2, the more abundant
-subunit in human T-lymphocytes (24), accelerates the functional
assembly of Kv1.3 channels. The ability of the Kv2 subunit to
enhance current levels of Kv1.3 may help to explain how the increase in
Kv2 subunit expression can up-regulate the expression of Kv1.3
channels in activated murine lymphocytes. The much greater increase in
Kv2 protein levels of mitogen-treated T-cells in mouse (24),
compared with human (Fig. 6), is consistent with the differential
increase in K+ current observed in mitogen-treated T-cells
in these two organisms. In fact, although K+ current levels
in human mitogen-treated T-cells increase roughly 2-fold, this effect
is immediate (19), unlike in mouse (20), ruling out transcriptional or
translational regulation as the means by which the K+
current level increases. The differences in -subunit regulation in
mice and humans may account for the vast difference in the extent to
which Kv1.3 K+ conductance is up-regulated in activated
T-cells in these two organisms.
ACKNOWLEDGEMENT
FOOTNOTES
REFERENCES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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R. Vicente, A. Escalada, M. Coma, G. Fuster, E. Sanchez-Tillo, C. Lopez-Iglesias, C. Soler, C. Solsona, A. Celada, and A. Felipe Differential Voltage-dependent K+ Channel Responses during Proliferation and Activation in Macrophages J. Biol. Chem., November 21, 2003; 278(47): 46307 - 46320. [Abstract] [Full Text] [PDF]
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L. Conforti, M. Petrovic, D. Mohammad, S. Lee, Q. Ma, S. Barone, and A. H. Filipovich Hypoxia Regulates Expression and Activity of Kv1.3 Channels in T Lymphocytes: A Possible Role in T Cell Proliferation J. Immunol., January 15, 2003; 170(2): 695 - 702. [Abstract] [Full Text] [PDF]
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K. McCormack, J. X. Connor, L. Zhou, L. L. Ho, B. Ganetzky, S.-Y. Chiu, and A. Messing Genetic Analysis of the Mammalian K+ Channel beta Subunit Kvbeta 2 (Kcnab2) J. Biol. Chem., April 5, 2002; 277(15): 13219 - 13228. [Abstract] [Full Text] [PDF]
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R. Bahring, C. J. Milligan, V. Vardanyan, B. Engeland, B. A. Young, J. Dannenberg, R. Waldschutz, J. P. Edwards, D. Wray, and O. Pongs Coupling of Voltage-dependent Potassium Channel Inactivation and Oxidoreductase Active Site of Kvbeta Subunits J. Biol. Chem., June 15, 2001; 276(25): 22923 - 22929. [Abstract] [Full Text] [PDF]
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