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J Biol Chem, Vol. 275, Issue 13, 9358-9362, March 31, 2000
From the Department of Pharmacology, Tohoku University School of
Medicine, 2-1 Seiryomachi Aobaku, Sendai 980-8575, Japan and
¶ Department of Pharmacology, Yamagata University School of
Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
N-type inactivation of rat Kv1.4 channels with
one, two, or four inactivation balls was investigated using homogeneous
populations of channels expressed in Xenopus oocytes.
Tandem dimeric and tetrameric constructs of Kv1.4 were made. Channels
encoded by tandem cDNAs Kv1.4-Kv1.4 Isolation of the clone encoding the Shaker
K+ channel from Drosophila has made it possible
to examine the molecular mechanism of N-type inactivation of A-type
K+ channels. The Shaker K+ channel
provided the first example of "ball and chain"- type inactivation,
which was originally proposed for voltage-dependent Na+ channels (1). The mechanisms of fast inactivation
observed in mammalian homologues of Shaker K+
channels have been proved to be the same as that of Shaker
K+ channels (2-5). K+ channels are composed of
four In a previous study (20), we made dimeric cDNA by tandem linkage of
the rapidly inactivating K+ channel clone Kv1.4 and the
noninactivating K+ channel clone Kv1.2 isolated from rat
heart. The dimeric cDNA encodes a hybrid channel that is composed
of Kv1.4 and Kv1.2 subunits with 1:1 stoichiometry. In the hybrid
channel there are two inactivation balls tethered to Kv1.4 subunits.
This approach revealed that in the hybrid channel inactivation is
determined not only by inactivation balls but also by the composition
of the pore-forming In this study we investigated how inactivation kinetics are regulated
by inactivation balls in rat Kv1.4 channels. For this purpose we made
tandem dimeric and tetrameric cDNAs from a Kv1.4 clone, and
homogeneous populations of K+ channels with one, two, or
four inactivation balls were expressed in Xenopus oocytes.
The ratio of the inactivation rate constant of the channel with one or
two inactivation balls to the Kv1.4 channel with four balls was larger
than expected. This suggests that in rat Kv1.4 channels some
interaction may exist between inactivation balls although previous
studies in Shaker K+ channels have suggested
that inactivation balls are independent (21, 22).
Dimeric cDNA Construction--
Two different dimeric
cDNA constructs were generated from the cDNA clone, Kv1.4
isolated from rat cardiac muscle (23). One was generated by tandem
linkage of two Kv1.4 sequences and another by linking the 3' end of the
first Kv1.4 to the 5' end-deleted Kv1.4. Kv1.4 cDNA coding for the
first (the 5' site) subunit of the tandem dimer was altered on the 3'
end by introduction of the linker sequence recognized by
SpeI, which replaced the stop codon nucleotides 1963-1965.
PCR1 amplification was
performed to generate the BstEII (nucleotide 1560)/SpeI fragment (fragment I). Fragment I was ligated
back into Kv1.4 in pBluescript vector (Stratagene, La Jolla, CA, USA) (intermediate construct). For the second position of the tandem dimers,
Kv1.4 cDNA was altered at the 5' end or nucleotide 436G (N-terminal
end of assembly domain) by adding the SpeI restriction site.
The SpeI/MluI (nucleotide 531) fragments were
amplified by PCR (fragments II and II'). Fragments II or II' and the
MluI/NotI fragment from Kv1.4 in pBluescript were
ligated into the corresponding sites of the 3' end-modified
intermediate construct digested with SpeI and
NotI. The tandem dimers generated in this manner were Kv1.4-Kv1.4 (full dimer) and Kv1.4-Kv1.4 Tetrameric cDNA Construction--
The tandem tetrameric
cDNA of Kv1.4 was constructed using Kv1.4-Kv1.4 Expression of Dimeric and Tetrameric Constructs and Current
Recording--
The pBluescript vectors containing the dimeric or
tetrameric constructs were linearized with EcoRI, and cRNAs
were prepared from these templates with T7 RNA polymerase using
MEGAscript RNA synthesis kit (Ambion, Austin, TX). Procedures for
preparation of Xenopus oocytes and injection of the
synthesized cRNAs were the same as those described previously (20). The
K+ currents were recorded by conventional
two-microelectrode voltage clamp with 3 M KCl filled
electrodes. The bath recording solution consisted of ND 96 (mM): NaCl,
96; KCl, 2; CaCl2, 1.8; MgCl2, 1; Hepes, 5; pH
7.5 adjusted with NaOH. All electrophysiological measurements were
carried out at room temperature (21 ± 1 °C).
Data Analysis--
Statistical analysis of the data was
performed with analysis of variance and significance isolated by
Dunnett's test. Values in the text, figures, and tables are given as
means ± S.E.
The schematic diagrams of the polypeptides encoded by tandem
dimeric and tetrameric Kv1.4 cDNAs are shown in Fig.
1A. Polypeptide (Kv1.4-Kv1.4)
encoded by the full tandem dimeric cDNA has amino acid sequence
corresponding to ball and chain region in the second (3' site) subunit
as well as in the first subunit. On the other hand, polypeptide
(Kv1.4-Kv1.4 The currents observed when cRNAs of the tandem dimeric and tetrameric
constructs were injected into the oocytes showed similar characteristics to Kv1.4 (Fig. 2,
B-E). The current-voltage relationships of
Kv1.4-Kv1.4, Kv1.4-Kv1.4
Changes in the Inactivation of Rat Kv1.4 K+ Channels
Induced by Varying the Number of Inactivation Particles*
,
, and
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DISCUSSION
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1-145 and
Kv1.4-[Kv1.41-145]3 have two or only one tethered
inactivation ball, respectively, whereas Kv1.4 itself encodes channels
having four inactivation balls. The time constants for inactivation of
macroscopic currents were increased significantly as the number of
inactivation balls was decreased, whereas the time constants for
recovery from inactivation were not modified. The ratios of the rate
constants of inactivation (kinact) of
Kv1.4-Kv1.41-145 and Kv1.4-[Kv1.41-145]3 channels
to that of the Kv1.4 channel were 0.65 and 0.4, respectively, whereas
the ratios of the rate constant of recovery
(krec) of these channels to that of Kv1.4 were
almost unity. The rate constants kinact for
channels having two and four inactivation balls are smaller than those
that would be expected if inactivation balls on each channel are
independent, suggesting some interaction occurs between inactivation
balls. Furthermore, noninactivating current became apparent as the
number of inactivation balls on a channel was decreased.
INTRODUCTION
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-subunits (6-12), each of which is encoded by a K+
channel gene. Functional K+ channels are also formed by the
assembly of different subunits encoded by different genes within
the same K+ channel subfamily (13-19).
-subunits, of which intracellular loops form the
receptor sites for inactivation balls. It is, however, inappropriate to
use hybrid channels to examine the relationship between inactivation
kinetics and the number of inactivation balls, because the
heterogeneity of the receptors for inactivation balls has, in itself, a
certain effect on inactivation kinetics.
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1-145 (partial dimer). The
procedure for constructing tandem dimeric cDNA, Kv1.4-Kv1.2 was
described in detail elsewhere (20).
1-145. Two
dimeric cDNAs were linked by six nucleotides recognized by
SplI. 5' and 3' ends of partial tandem dimers were altered
by PCR for introduction of the SplI site. PCR was performed using a sense oligonucleotide containing the BstEII site and
an antisense oligonucleotide containing SplI and
EcoRI sites and the last 21 nucleotides. The PCR product was
ligated into a partial dimeric cDNA in pBluescript digested with
BstEII and EcoRI (3' end modified partial dimeric
cDNA). A fragment was amplified by PCR with a sense primer
containing HindIII and SplI sites, and 21 nucleotides from 436G and an antisense primer containing the MluI site in Kv1.4. The amplified fragment was ligated into
the corresponding site in a partial dimeric cDNA following
digestion with HindIII and MluI (5' end modified
partial dimeric cDNA). Both 3' and 5' end modified partial dimeric
cDNAs were digested by SplI and NotI and
ligated into the complete tandem tetrameric constructs.
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1-145) from the partial tandem dimeric cDNA lacks
amino acid sequence corresponding to ball and chain region in the
second subunit. Channels formed by the partial tandem polypeptide of
Kv1.4 have two tethered inactivation balls, whereas the full tandem
dimeric cDNA encodes channels with two tethered inactivation balls
and two positioned in the loops connecting the subunits (Fig.
1B, b and c). Because the polypeptide
encoded by the tandem tetrameric cDNA lacks amino acid sequences
preceding the assembly domain in each subunit except the first one,
there is only one inactivation ball per channel (Fig. 1B,
d).
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Fig. 1.
Polypeptides encoded by tandem dimeric and
tetrameric cDNAs and proposed assembly of the polypeptides to form
channels. A, diagrams of Kv1.4-Kv1.4,
Kv1.4-K1.4 1-145, Kv1.4-[K1.41-145]3, and
Kv1.4-Kv1.2 polypeptides. Darkened segments in each polypeptide
represent the six putative transmembrane segments. In the diagram of
Kv1.4-K1.41-145 and Kv1.4-[K1.41-145]3 the
deleted amino acids 1 through 145 are indicated by a fine
line. B, cartoons illustrating the proposed assembly of
the tetrameric channels formed from Kv1.4 and the four tandem
cDNAs. The channels formed from Kv1.4-Kv1.41-145 (c)
and Kv1.4-Kv1.2 (e) have two tethered inactivation balls on
each channel. The channels formed from Kv1.4 (a) and
Kv1.4-Kv1.4 (b) have four inactivation balls, but two
inactivation balls are positioned in the loop connecting the subunits
in the Kv1.4-Kv1.4 dimer. Kv1.4-[Kv1.41-145]3 forms
channels that have only one tethered inactivation ball on each channel
(d), because the ball and chain region was deleted in all
the constituent subunits except the first one.
1-145,
Kv1.4-[Kv1.41-145]3, and Kv1.4-Kv1.2 (hybrid)
channels were quite similar to Kv1.4. However, the currents generated
by Kv1.4-Kv1.4, Kv1.4-Kv1.41-145, and
Kv1.4-[Kv1.41-145]3 inactivated more slowly than
Kv1.4. A comparison of the current decay for Kv1.4, Kv1.4-Kv1.4,
Kv1.4-Kv1.41-145, Kv1.4-[Kv1.41-145]3, and
Kv1.4-Kv1.2 at a potential of +20 mV is shown in Fig.
3. Time constants 
inact
for test pulses to +20 mV are presented in Table I. The time constants of inactivation for
Kv1.4-Kv1.41-145 and Kv1.4-[Kv1.41-145]3 were
significantly increased compared with Kv1.4, whereas the difference in
time constants between Kv1.4 and Kv1.4-Kv1.4 was not statistically
significant. The time constant for Kv1.4-Kv1.2 did not differ from that
for Kv1.4 as described previously (20) (Table I). In addition to the
slowing of current decay, inactivation became less complete as the
number of inactivation balls on a channel was decreased. It was
estimated from the exponential fits of current decay that
noninactivating currents generated by Kv1.4, Kv1.4-Kv1.4,
Kv1.4-Kv1.41-145, and Kv1.4-[Kv1.41-145]3 were
about 3, 6, 9, and 18% of the peak currents, respectively.
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Fig. 2.
Macroscopic currents recorded by a
two-microelectrode voltage clamp from injected Xenopus
oocytes. A, B, C,
D, and E represent current traces recorded from
the oocytes injected with synthesized cRNAs of Kv1.4, Kv1.4-Kv1.4,
Kv1.4-Kv1.4 1-145, Kv1.4-[Kv1.41-145]3, and
Kv1.4-K1.2, respectively. Oocytes were held at -80 mV and depolarized
to test potentials for 400 ms varying from 
70 mV to +40 mV in 10 mV
increments. Depolarization steps were applied at an interpulse interval
of 30 s. Current traces elicited by steps to 40, 20, 0, +20,
and +40 mV are shown in each panel. The current-voltage relationships
of the peak currents measured at each test potential plotted, are
presented on the right of the current traces. The average peak currents
at test pulses to +20 mV for Kv1.4, Kv1.4-Kv1.4, Kv1.4-Kv1.41-145,
Kv1.4-[Kv1.41-145]3, and Kv1.4-Kv1.2 were 3.7 ± 0.5 (n = 26), 2.1 ± 0.4 (n = 16),
2.5 ± 0.4 (n = 23), 2.0 ± 0.2 (n = 30), and 5.8 ± 1.2 (n = 8)
µA, respectively. Records were obtained 3-6 days after injection of
oocytes with cRNAs in vitro transcribed from respective
cDNAs. Calibration bars are 100 ms and 1 µA.
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Fig. 3.
Time courses of inactivation in the expressed
channels. Normalized macroscopic currents from Xenopus
oocytes in Fig. 1, A-E are shown. Currents
evoked by a test potential to +20 mV for 400 ms from each channel are
normalized and superimposed to illustrate the differences in the time
course of current decay. Current traces are named as follows:
a, Kv1.4; b, Kv1.4-Kv1.4; c,
Kv1.4-Kv1.4 1-145; d,
Kv1.4-[Kv1.41-145]3; and e, Kv1.4-Kv1.2.
Mean values of time constants for macroscopic inactivation for each
channel are presented in Table I.
Time constants for inactivation and recovery from inactivation of
macroscopic currents
inac) were measured from
exponential fits to the onset of inactivation of currents recorded from
oocytes injected with the indicated cRNAs. All of the currents were
best fitted by a single exponential. Time constants of recovery from
inactivation (rec) were calculated by fitting curves of
fractional recovery (means ± S.E.). The numbers given in
parentheses represent oocytes tested. Differences between channels were
analyzed by variance, and the statistical significance was isolated
using Dunnett's test.
Time courses of recovery from inactivation for the channels are shown
in Fig. 4. Recovery from inactivation was
significantly faster in the hybrid channel than in Kv1.4 channels.
There were no differences in the time constants for recovery between
Kv1.4 channels with different numbers of inactivation balls. Time
constants for recovery from inactivation rec of the
channels tested are presented in Table I.
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To gain a more precise insight into the inactivation process, we
estimated the microscopic rate constants of inactivation (kinact) and recovery from inactivation
(krec) for individual channels as described
previously (20). We calculated the values of
kinact only from the oocytes in which both the
time constants for inactivation and recovery from inactivation were
measured (Table II). The ratio of
kinact for Kv1.4-Kv1.41-145 to Kv1.4 is
0.65. This indicates that the microscopic inactivation rate constant of
the channel with two inactivation balls is more than half that of Kv1.4
channel with four inactivation balls. Furthermore, the ratio of
kinact for Kv1.4-[Kv1.41-145]3
to Kv1.4 is 0.4, indicating that the microscopic inactivation rate
constant of the channel with only one inactivation ball is larger than
one-fourth that of Kv1.4 channel. The kinact
value of the Kv1.4-Kv1.4 channel was smaller than that of the Kv1.4
channel, although both types of channels have the same number of
inactivation balls. When the values of kinact
were compared between Kv1.4-Kv1.41-145 and Kv1.4-Kv1.2 channels, it
became evident that kinact for the
Kv1.4-Kv1.41-145 channel is smaller than that of the hybrid
channel. This could be attributed to the difference in the composition
and the structure of the receptor sites for inactivation balls, because
Kv1.4-Kv1.41-145 and the hybrid channels have the same number of
inactivation balls.
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To further characterize the properties of the channels encoded by the dimeric and tetrameric cDNAs, the steady-state voltage dependence of their activation and inactivation was studied. The average values of the parameters are summarized in Table III. There were no differences between Kv1.4 channels with different numbers of inactivation balls except in the noninactivating component. A noninactivating component increased as the number of inactivation balls on each channel was decreased.
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Inactivation of Kv1.4 channel is caused by occlusion of the intracellular mouth of the pore by the inactivation ball located in the N terminus of the polypeptide as in the Shaker K+ channel (2, 5). The ball binds to its receptor via electrostatic and hydrophobic interactions. As polypeptides of the principle subunit of voltage-gated K+ channels form tetramers (6-9), it is evident that Kv1.4 has four inactivation balls on each channel when expressed alone.
Relationship between inactivation balls and rate of inactivation has been examined using Shaker B channel. To investigate the relationship, MacKinnon et al. (21) studied channels carrying a specific mutation in a single subunit quantitatively by monitoring scorpion toxin sensitivity. On the other hand, Gomez-Lagunus and Armstrong (22) used the approach of gradually removing inactivation with intracellular papain. However, these analytical procedures were based on the assumption that co-assembly of wild-type and mutated subunits or the predicted fraction of channels with various numbers of inactivation balls after protease treatment obeys the rules of a binomial distribution. In this study we have investigated the role of inactivation balls in the rate of inactivation by use of a different strategy than these reports. This approach seems to have the advantage that interpretation of the results does not need any assumptions about subunit stoichiometry. To constrain the number of inactivation balls in the expressed channels, dimeric and tetrameric cDNAs were constructed from rat cDNA clone Kv1.4, which encode two or four Kv1.4 subunits on a single polypeptide chain (Fig. 1A). It has been demonstrated that two polypeptides encoded by the dimeric cDNA construct can assemble to form functional channels with tetrameric structure (7, 11, 18, 24, 25). For K+ channels, tetrameric cDNA constructs also encode functional channels resembling, in their electrophysiological properties, those expressed from monomers (7, 11, 24). Therefore, it is probable that the channels have two or only one inactivation ball when the partial tandem dimeric or tetrameric cDNAs of Kv1.4 are expressed in Xenopus oocytes.
The voltage dependence of activation and inactivation of the channels with different numbers of inactivation balls is similar, suggesting that alterations in inactivation should be attributed to the difference in the number of inactivation balls. We have demonstrated directly that the channels that have only one ball can inactivate, which is consistent with the results with Shaker K+ channels described by MacKinnon et al. (21). However, inactivation of the current from the channel with only one ball was incomplete in our experimental conditions, compared with the channel with four balls. Increases in the noninactivating currents may be due to less frequent occlusion of the pore by a smaller number of particles. Transitions between open and closed states before entering the inactivated state might be another possibility.
The ratios of the inactivation rate constants from the channel with one and two balls were larger than one-fourth and one-half that of the channel with four balls, respectively. MacKinnon et al. (21) described that in Shaker K+ channels the rate constant for the channel with a single gate was one-fourth that of channels with four gates and suggested independence of each inactivation gate. We considered the following possibilities that might account for the difference. First, there may be some interaction between inactivation balls: electrostatic repulsion between balls due to positive charges on their surfaces could decrease access of inactivation balls to their receptor sites when a channel has more than a single ball. Second, slow recovery of Kv1.4 may result in larger rate constants than expected for the channels with one and two inactivation balls. Recovery from inactivation of Kv1.4 is much slower than that of the Shaker K+ channel. Kv1.4 has more positive charges than the Shaker K+ channel in its ball structure, which could result in a higher affinity of the inactivation ball for its receptor. There is also another possibility that might arise from the experimental strategy. Structural changes induced by linkage of the subunits in a single polypeptide chain might alter accessibility of inactivation balls to their receptor sites.
The channels that have two tethered balls and two in the connecting loop showed an inactivation rate constant that was intermediate between channels with four tethered balls and those with two balls. This indicates that the ball structure positioned in the loop also functions as an inactivation gate, but its access to the receptor was decreased due to restricted movement.
In this study we have isolated the current of Kv1.4 channel with a
single or two inactivation balls for the first time by expressing
homogeneous populations of channels in Xenopus oocytes. It
was demonstrated that rat Kv1.4 channel could inactivate even with only
a single inactivation ball, although inactivation was not complete. The
calculated microscopic rate constants for inactivation of the channels
with a single and two inactivation balls were larger than would be
expected if inactivation balls were independent, suggesting the
possibility of some interaction between inactivation balls. Single
channel analysis will provide unequivocal estimation of differences in
microscopic rate constants of inactivation and the mechanism underlying
the noninactivating fraction of the currents.
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ACKNOWLEDGEMENTS |
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We thank Dr. Michael J. Seagar (INSERM U464, Faculte de Medecine Secteur Nord, Marseille, France) for critical reading of the manuscript.
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FOOTNOTES |
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* This work was supported by Grant-in-aid for Scientific Research (07670099, 10670079) from the Ministry of Education, Science, Sports and Culture, Japan.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: Dept. of Pharmacology, Tohoku University School of Medicine, 2-1 Seiryomachi Aobaku, Sendai 980-8575, Japan. Tel.: 81-22-717-8063; Fax: 81-22-717-8065; E-mail: nu09-23@mail.cc.tohoku.ac.jp.
Present address: Discovery Research Laboratory, Tanabe Seiyaku Co.,
Ltd., 2-2-50, Kawagishi, Toda 335-8505, Japan.
Present address: Kohnan Hospital, 4-20-1 Nagamachiminami,
Taihakuku, Sendai 982-0012, Japan.
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ABBREVIATIONS |
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The abbreviation used is: PCR, polymerase chain reaction.
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ABSTRACT
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, Kv1.4; 
, Kv1.4-Kv1.4; 
,
Kv1.4-Kv1.4
, Kv1.4-[Kv1.4
, Kv1.4-Kv1.2.
1 and