Two Regions of Sulfonylurea Receptor Specify the Spontaneous
Bursting and ATP Inhibition of KATP Channel Isoforms*
Andrey P.
Babenko
,
Gabriela
Gonzalez, and
Joseph
Bryan
From the Department of Cell Biology, Baylor College of Medicine,
Houston, Texas 77030
 |
ABSTRACT |
KATP channels are
heteromultimers of KIR6.2 and a sulfonylurea receptor, SUR,
an ATP binding cassette (ABC) protein with several isoforms.
KIR6.2 forms a channel pore whose spontaneous activity and
ATP sensitivity are modulated by the receptor via an unknown interaction(s). Side by side comparison of single-channel kinetics and
steady-state ATP inhibition of human
-cell, SUR1/KIR6.2, versus cardiac, SUR2A/KIR6.2 channels
demonstrate that the latter have a greater mean burst duration and open
probability in the absence of nucleotides and ~4-fold higher
IC50(ATP). We have used matched chimeras of SUR1 and SUR2A
to show that the kinetics, which determine the maximal open probability
(Pomax), and the ATP sensitivity are functionally separable
and to identify the two segments of SUR responsible for these isoform
differences. A region within the first five transmembrane domains
specifies the interburst kinetics, whereas a C-terminal segment
determines the sensitivity to inhibitory ATP. The separable effects of
SUR on ATP inhibition and channel kinetics implies that the cytoplasmic C terminus of SUR either directly modulates the affinity of a weak ATP
binding site on the inward rectifier or affects linkage between the
binding site and the gate. This is the first identification of parts of
an ABC protein that interact with an ion channel subunit to modulate
the spontaneous activity and ATP sensitivity of the heteromeric channel.
 |
INTRODUCTION |
KATP channels are heteromultimers of a sulfonylurea
receptor, SUR,1 a member of
the ATP binding cassette (ABC) superfamily, and a potassium inward
rectifier, KIR6.2 (1-4). Both subunits are required to
assemble channels with high sensitivity to ATP and the spontaneous bursting analyzed using single-channel recording originally on pancreatic
-cells (5) and cardiac myocytes (6). A minimal description of the gating kinetics in the absence of nucleotides requires time constants,
O and
Cf, which
specify the distributions of open and intraburst closed states and are
dependent on the K+ driving force and at least one
additional time constant,
Cs to describe interburst
closures (6, 7). Although the structure, numbers of binding site(s) for
inhibitory ATP, and ATP-bound closed states have not been determined,
ATP shortens the mean burst duration and reduces the open channel
probability (Po) mainly by increasing the fraction of time the channel
spends in long interburst intervals but does not block the open channel
pore, alter the unitary conductance, or have significant effects on the
intraburst kinetics (reviewed, for example in Ref. 8). Studies on
KATP channels in pancreatic
-cells and cardiac myocytes
(reviewed, for example, in Refs. 3, 4, and 9), and limited analyses of
recombinant SUR1/KIR6.2 versus
SUR2A/KIR6.2 channels (3, 10) indicate these two channels differ in their interburst kinetics and ATP sensitivity in addition to
their pharmacology (4, 10). The side by site comparison given here
confirms these preliminary observations (3, 10), demonstrating that the
SUR1/KIR6.2
-cell and SUR2A/KIR6.2 cardiac KATP channels have different interburst kinetics and
steady-state IC50(ATP) values of ~5 versus
~25 µM, respectively. Co-expression of matched chimeras
of human SUR1 and SUR2A with KIR6.2 delineates two segments
of SUR within the first 5 transmembrane domains and in the C terminus
that specify the pattern of spontaneous bursting and sensitivity to
inhibitory ATP, respectively. This is the first identification of the
molecular determinants within SUR, an ABC protein, that interact with
KIR6.2 to specify the intrinsic activity and ATP
sensitivity of the heteromeric channel isoforms. The results suggest
that allosteric interactions play an important role in the unique ATP
inhibitory gating displayed by this channel family.
 |
EXPERIMENTAL PROCEDURES |
Molecular Biology--
The human SUR1 and SUR2A cDNAs and
their genes have been described previously (3). Human
KIR6.2 was obtained from genomic DNA by PCR and was
sequenced on both strands. The matched SUR chimeras were engineered
using naturally occurring endonuclease restriction sites in the SUR1
and SUR2A cDNAs where possible. When necessary, matching
restriction sites were engineered into the complementary cDNA using
overlapping PCR primers. These were combined with appropriate flanking
forward and reverse primers including unique restriction enzyme sites.
Two amplifications were carried out; the first set of reactions matched
the forward and reverse flanking primers with the appropriate
overlapping primer. The resulting PCR products were purified by agarose
gel electrophoresis, mixed, and used as the template for the second PCR
reaction with the flanking primers. The product of the second reaction
was cut with an appropriate pair of restriction enzymes and used to
replace the corresponding wild-type fragment. The desired SUR fragments
were then swapped using standard subcloning methods. All the PCR
products and restriction sites were sequenced to verify the
constructions. The restriction sites used, the amino acids, and their
positions in the SUR1 and SUR2A proteins are shown in Table I and are
illustrated schematically in Fig. 3. The swaps of the smaller segments
at the C-terminal end of the receptor were done using overlapping PCR
primers as described above.
Transfection and Cultivation of Cells for Electrophysiological
Experiments--
Approximately 1.8×105 COSm6 cells/35-mm
dish were transfected with 1 µg of SUR plasmid and/or 1 µg of the
wild-type or modified KIR6.2 plasmid and 0.5 µg of a
green fluorescent protein (pGreen LanternTM-1,
Life-Technologies, Inc.) plasmid. Transfections were done using FuGene6
following the manufacturers directions (Roche Molecular Biochemicals).
Transfected cells were cultured overnight, trypsinized, and replated on
glass coverslips. Cells expressing green fluorescent protein as a
marker were selected for analysis unless otherwise noted. COSm6 cells
were used in these studies because previous work has shown they have no
endogenous SUR1 detectable with radiolabeled glibenclamide binding
assays (11), and expression of either SUR1 or KIR6.2 alone
produces no novel K+ currents detectable by
86Rb+ efflux assays or single-channel recording
(9, 12).
Patch-clamp Recording and Single-channel Current
Analysis--
The properties of the reconstituted channels were
analyzed in inside-out configurations using the patch-clamp technique
as described previously (9). All experiments were done at 23-24 °C.
Pipettes were filled with the quasi-physiological external solution
containing 140 mM NaCl, 5 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM HEPES, pH 7.4 (NaOH) or the K+-rich
external solution containing: 145 mM KCl, 1 mM
MgCl2, 1 mM CaCl2, 10 mM HEPES, pH 7.4 (KOH) and had a resistance of 4-8 megaohms. Smaller pipettes were used in some experiments to record single-channel currents. An internal solution, nominally
Mg2+-free, containing 140 mM KCl, 5 mM EDTA, 5 mM HEPES, 10 mM KOH, pH
7.2 (KOH) was used as the control bath solution. The disodium salt of
ATP and other compounds were from Sigma. Bathing solutions were applied
using a programmable rapid solution changer (RSC-200, Biologic Inc,
Claix, France). Quasi-steady-state sensitivity to inhibitory ATP was
estimated using experimental conditions and a protocol designed to
minimize variability in the apparent IC50(ATP) as described
previously (9). We were able to repeatedly apply the dose-response
protocol and observe stable sensitivity to inhibitory ATP for >30 min.
The maximal Po values were estimated from Gaussian fits to all-points
current-amplitude histograms constructed from continuous segments of
records activated immediately after patch excision. In all figures,
upward deflection of the current trace corresponds to outwardly
directed current, and the horizontal dotted lines show the level of
current when all KATP channels are closed. For single-
channel kinetics analysis using inwardly directed currents, only patch
current records with no superimposed openings were used in which the
cumulative Po increased linearly for more than a half-minute during
continuous recording immediately after patch isolation. For heteromeric
SUR/KIR6.2 channels displaying Po > 0.5, these
criteria were sufficient to be confident that only single channels
without significant run-down were being analyzed. The kinetic analysis
including the burst analysis at an optimal burst criteria was performed
using pClamp7 and BioQuest software as described previously (9).
Averaged data are expressed as means ±S.E. for n
5 with error bars equal to the S.E. unless otherwise noted. Significance
was evaluated using the Student's t test; differences with
values of p < 0.05 were considered to be significant.
 |
RESULTS |
SUR Isoforms Specify the Kinetics and ATP Inhibition of
KATP Channels--
A quantitative side by side comparison
of the kinetics and steady-state ATP-inhibition of human
SUR1/KIR6.2 and human SUR2A/KIR6.2 channels was
carried out to define the differences in gating and ATP sensitivity of
-cell and cardiac KATP channels. As shown in Fig.
1, the SUR2A/KIR6.2 channels
display longer bursts and spend less time in interburst gaps than the
SUR1/KIR6.2 channels, whereas the intraburst kinetics of
the two channels are indistinguishable. As a consequence, a hallmark of
the SUR2A/KIR6.2 channels is a higher Pomax
(0.91 ± 0.01 versus 0.64 ± 0.03 at
40 mV,
respectively). The SUR1/KIR6.2 channels, on the other hand,
are ~4-fold more sensitive to ATP than the SUR2A/KIR6.2
channels (IC50(ATP) = 5.9 ± 0.5 versus
23.4 ± 2.6 µM, see also Ref. 9). Both channel isoforms are significantly more sensitive to inhibitory ATP and both
have severalfold higher Pomax values than homomeric
KIR6.2 channels, 0.09 ± 0.01 and 221.1 ± 12.1 µM for the human KIR6.2
C35 channels, which
were analyzed in parallel ( Ref. 13, see also Refs. 9, 14-16).

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Fig. 1.
A comparison of single-channel kinetics and
ATP inhibition of SUR1/KIR6.2 versus
SUR2A/KIR6.2 channels. A, a
representative example of currents through SUR1/KIR6.2
(left) and SUR2A/KIR6.2 (right)
channels recorded at 40 mV with the K+-rich external
pipette and internal control solutions. The dwell time distributions
are shown below the traces. The mean burst duration at a
burst criterion of 2 ms, Tb2 ms, was <30 ms for all 4 patches containing a single SUR1/KIR6.2 channel but was
>298 ms for all 5 patches containing single SUR2A/KIR6.2
channels. B, the steady-state ATP inhibition of the
SUR1/KIR6.2 (upper trace) and
SUR2A/KIR6.2 (lower trace) channels was examined
as described under "Experimental Procedures." The mean
IC50(ATP) ± error values and a slope factor (h) obtained
from the best fit to a conventional pseudo-Hill equation using Origin
5.0 Professional (Microcal Software, Inc., Northampton, MA) are shown.
The IC50(ATP) values for the two channels are significantly
different and markedly lower than determined for human
KIR6.2 C35 channels shown for comparison.
|
|
Two Distinct Region of SUR Specify Spontaneous Bursting and ATP
Inhibition of KATP Channel Isoforms--
Matched pairs of
human SUR1 and SUR2A chimeras were co-expressed with KIR6.2
to delineate the regions of SUR that affect the interburst kinetics and
ATP inhibition of KATP channels. The chimeras were
generated by "swapping" progressively longer segments, chosen to
include the major structural features of SUR, as presented in Table
I and shown diagrammatically in Fig. 3.
Fig. 2 illustrates the analytical
strategy using one pair of chimeras in which the N-terminal segment of
SUR1 (or SUR2A) that included the first 29 amino acids and the first
two sets of transmembrane domains, TMDI-N and TMDI-C, were swapped onto
the reciprocal C-terminal segment of SUR2A (or SUR1) including NBF1,
TMDII, NBF2, and the C terminus. The SUR1~SUR2A/KIR6.2
channels displayed all the kinetic properties of the
-cell channel
but required ~4-fold more ATP for half-maximal inhibition. The
matched partner, SUR2A~SUR1/KIR6.2, displayed the closed
time distribution, high Pomax, and bursting pattern of a
cardiac KATP channel but was inhibited by ATP with an
IC50(ATP) value appropriate for the
-cell
KATP channel. The intraburst kinetics of the two chimeric
channels illustrated in Fig. 2 are the same as they are for the
channels assembled from the other matched pairs. Analysis of the other
pairs of chimeras (Fig. 3) demonstrated
that the TMDI-N segment determines the higher Pomax of the
cardiac channel, whereas the C-terminal region specifies the lower
IC50(ATP) of the
-cell channel. Swapping a 52-amino acid
segment, C52, the last 42 of which actually differ, was sufficient to
completely specify the IC50(ATP) value associated with the donor SUR isoform. Smaller swaps, 27- and 12-amino acids, respectively, C27 and C12, produced a graded effect, and, therefore, we have not
attempted to localize the molecular determinant(s) to a specific residue; rather, the results suggest the last 42 amino acids are important and may form a contact surface with KIR6.2.

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Fig. 2.
A comparative analysis of one pair of matched
chimeric SUR/KIR6.2 channels. A, a
schematic representation of one of the matched pairs of chimeric SURs,
which were co-expressed with wild type KIR6.2. The swapped
segments from SUR1 and SUR2A are shown in gray and
black, respectively. The chimeras are named, as illustrated,
according to which isoform contributed the N terminus. B, an
analysis of the closed time distributions for the two chimeric channels
used to evaluate differences in their kinetics, done as described in
Fig. 1A. Note the greater
Tb2 ms and significantly smaller slow
component of the closed time probability density function for the
SUR2A~SUR1/KIR6.2 versus
SUR1~SUR2A/KIR6.2 channel that determines its higher
Pomax (0.91 ± 0.01 versus 0.64 ± 0.03; n = 4 for both channels). C,
determination of the ATP inhibition of SUR2A~SUR1/KIR6.2
(upper trace and open squares) and
SUR1~SUR2A/KIR6.2 (lower trace and open
circles) channels demonstrates that this pair of chimeric channels
has mixed properties. The SUR2A~SUR1/KIR6.2 channels show
the kinetics of cardiac channels but are inhibited with the
IC50(ATP) of -cell KATP channels, whereas
the SUR1~SUR2A/KIR6.2 channels have -cell kinetics and
the IC50(ATP) of cardiac channels. ATP inhibition was
analyzed as in Fig. 1B.
|
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Fig. 3.
Delineation of the SUR segments that specify
the differences in kinetics and ATP inhibition of two KATP
channel isoforms. The top panel shows the analysis of
the Pomax and IC50(ATP) for chimeric channels
assembled from wild type KIR6.2 and each of the SUR
constructs shown in the lower panel. The segments from SUR1
are shown in white and from SUR2A in gray. Chim
III and Chim XI were presented as SUR2A~SUR1/KIR6.2
and SUR1~SUR2A, respectively, in Fig. 2. The values in parentheses
give the number of ATP dose responses/single-channel current analyses
using different patches. Error bars = S.D. The presence
of the last 42 amino acids (a/a) of SUR1, the C52 swap, is
sufficient to confer the IC50(ATP) value of the C52 donor
SUR isoform. Smaller swaps, C27 and C12, give IC50(ATP)
values intermediate between the host and donor isoforms. The presence
of the TMDI-N segment from SUR2A correlates with a higher
Pomax value. The Pomax values were determined
at 0 mV with the quasi-physiological external solution in the pipette
and the control internal solution in the bath.
|
|
The results show there are two structural elements of SUR critical for
determining the isoform-dependent components of gating and
its modulation by inhibitory ATP and that these elements are distinct
from the two nucleotide binding folds. This is consistent with
observations that mutations in the nucleotide binding folds (17-19),
including those which eliminate azido ATP labeling of SUR1 (20), do not
affect inhibition by ATP. In our hands, for example, the human
SUR1K719R/KIR6.2,
SUR1K719R/K1385R/KIR6.2, and
SUR1K1506A/KIR6.2 channels are all inhibited by
ATP with IC50(ATP) values of 5-7 µM (data
not shown).
 |
DISCUSSION |
This is the first identification of two segments of the
sulfonylurea receptor that specify the intrinsic activity and ATP sensitivity of the inward rectifier subunit of KATP
channels. The results show that the modulation of channel kinetics and
apparent sensitivity to inhibitory ATP are separable. Recent reports
have focused on the behavior of the homomeric KIR6.2
channels that can be studied either by removing an endoplasmic
reticulum retention signal(s) (as shown by B. Schwappach, N. Zerangue,
Y. N. Jan, and L. Y. Jan (21)) from the C terminus of
KIR6.2 (14, 15) or by strong overexpression (16). Although
the homomeric channels display the wild type unitary conductance and
are weakly inhibited by ATP, they lack the hallmark properties of
native, heteromeric KATP channels including a high open
probability, correct bursting, high sensitivity to ATP, and
responsiveness to sulfonylureas, potassium channel openers, and MgADP
(14, 15). The properties of the homomeric channels are unlike any known
native K+ channels, indicating their physiological
relevance is questionable. Co-expression of KIR6.2 with a
SUR, on the other hand, generates a K+ conductance that
accurately reflects those found in a variety of different tissues with
the isoform or tissue-specific properties being specified by the SUR
involved. This report provides evidence for allosteric interactions
between KIR6.2 and two regions of SUR that are involved in
two defining properties of KATP channels, their spontaneous
bursting behavior and ATP sensitivity. TMDI-N contains a critical
determinant of bursting behavior, whereas the last 42 amino acids of
SUR specify the effect of ATP on gating. These results do not
contradict previous reports that mutations in the nucleotide binding
folds of SUR have negligible effects on the ATP inhibition of
KATP channels; rather, together the two results indicate
that whereas ATP binding and possible hydrolysis on SUR is not required
for ATP inhibition, interaction of KIR6.2 with other
regions of the receptor are critical for normal ATP inhibitory gating.
The chimeric channel experiments provide additional insight into the
mechanism of inhibition of KATP channels by ATP and imply SUR either modulates the affinity of KIR6.2 for ATP or
alters a link between the nucleotide binding site and the gate. We
develop the following argument using a minimal linear kinetic scheme
for KATP channel gating based on a simple model introduced
originally by Gillis et al. (22).
As the intraburst transitions between C1 and O,
specified by
O and
Cf, are the same for
the two channels (Fig. 1), the higher Pomax of the
SUR2A/KIR6.2 channels implies the cardiac channel will
spend less time in interburst closed states that bind ATP. Therefore,
the reduced apparent sensitivity of the SUR2A/KIR6.2 channels versus the SUR1/KIR6.2 channels to ATP
could be attributed solely to a reduction in the fraction of time the
former channel spends in interburst closed states. If this were
correct, the SUR isoforms could modulate the apparent ATP sensitivity
of KIR6.2 solely through their effect on the transition
from the open state to long-lived closed states. Although this would be
consistent with the observation that the TMDI-N segment is a critical
determinant of bursting behavior, it cannot explain the observation
that SUR can modulate the two properties independently with the C
terminus of SUR, determining the apparent ATP sensitivity of the
chimeric channels without substantially altering their bursting. This
argument is consistent with the observation that homomeric
KIR6.2
C channels have a reduced sensitivity to ATP (14,
15), yet spend a greatly increased fraction of time in interburst
closed states proposed to bind ATP (13, 15, 23). Thus the differences
in ATP sensitivity of the KATP channel isoforms that are
attributable to SUR and the enhancement of ATP sensitivity seen when
KIR6.2 is co-expressed with a SUR cannot be due solely to
changes in channel kinetics that affect the occupancy of interburst
closed states that bind ATP, as has been suggested from studies on
several KIR6.2 mutations (15, 24-26) and N-terminal
truncations of KIR6.2 (23) that produce parallel increases
in Pomax and IC50(ATP). These results imply
that SUR must either directly modulate the affinity of
KIR6.2 for ATP in closed state or affect the linkage
between the binding site(s) and the gate. We hypothesize that
modulation of the affinity of KIR6.2 for ATP by SUR could
result either from allosteric interactions or by formation of a shared
ATP binding site. Further studies including direct measurement of ATP
binding are needed to resolve these possibilities.
 |
Acknowlegments |
We thank Dr. Lydia Aguilar-Bryan for helpful
discussion, Li-Zhen Song for technical assistance, and other members of
the Baylor Group for encouragement.
 |
FOOTNOTES |
*
This work was supported by Juvenile Diabetes Foundation
International Grant 397003 (to A. P. B.) and National Institutes of Health Grants DK44311 and DK52771 (NIDDKD) (to J. B.).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: Tel.: 713-798-4996;
Fax: 713-970-0545; E-mail: ababenko{at}bcm.tmc.edu.
 |
ABBREVIATIONS |
The abbreviations used are:
SUR, sulfonylurea
receptor;
ABC, ATP binding cassette;
NBF, nucleotide binding fold;
Pomax, maximal open probability;
IC50(ATP), IC50 value for ATP;
TMD, transmembrane domain;
PCR, polymerase chain reaction.
 |
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