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J. Biol. Chem., Vol. 275, Issue 41, 31563-31566, October 13, 2000

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ACCELERATED PUBLICATION
Hetero-concatemeric K_IR6.X₄/SUR1₄ Channels Display Distinct Conductivities but Uniform ATP Inhibition^*

Andrey P. Babenko, Gabriela C. Gonzalez, and Joseph Bryan

From the Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

Received for publication, August 15, 2000

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

K_IR6.1 and K_IR6.2 are the pore-forming subunits of K_NDP, the nucleotide-diphosphate-activated K_ATP channels, and classical K_ATP channels, respectively. "Hybrid" channels, in which the structure is predetermined by concatemerizing K_IR6.1 and K_IR6.2, exhibit distinct conductivities specified by subunit number and position. Inclusion of one K_IR6.2 is sufficient to open K_IR6.X-X-X-X/SUR1₄ in the absence of nucleotide stimulation through sulfonylurea receptor-1 (SUR1). ATP inhibited the spontaneous bursting of hybrid channels with an IC_50(ATP) ~10⁵ M, similar to that of K_IR6.2₄-containing channels. These findings and a transient increase in K_NDP channel activity following rapid wash-out of MgATP suggested that K_IR6.1 is not ATP-insensitive as previously believed. We propose that SUR-dependent, inhibitory ATP-enhanced interactions of the cytoplasmic domains of both K_IR6.1 and K_IR6.2 stabilize a closed form of the M2 bundle in the gating apparatus.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Combinations of K_IR6.1 or K_IR6.2 with SUR1,¹ SUR2A, or SUR2B determine the classic subtypes of (K_IR6.X/SUR)₄ channels (1). The association of the K_IR tetramer with four SURs masks endoplasmic reticulum retention signals on both subunits, permitting surface expression of tetradimeric K_ATP channels (2).

Current evidence indicates the extracellular loops of K_IR6.X specify an ~2-fold difference in the unitary conductance, g, of K_IR6.1 versus K_IR6.2-based channels, whereas the K_IR cytoplasmic domains determine the nucleotide and Mg²⁺ requirements for channel opening (3-5). K_IR6.1-based channels are closed in the absence of nucleotides, but are strongly activated by Mg²⁺-nucleotide-diphosphates (maximally by ~10 mM MgUDP) and have been termed K_NDP channels (6). The substantial activity of K_NDP channels in millimolar MgATP suggested that K_IR6.1, in contrast to K_IR6.2, does not interact with inhibitory ATP (7, 8), although the analysis of inhibition of these channels by ATP is complicated by a requirement for stimulatory Mg²⁺-nucleotides. Unlike K_NDP, K_IR6.2-based channels burst continuously in nucleotide-free solutions, and homomeric K_IR6.2 channels (9), lacking the RKR retention sequence, reach the surface in the absence of SUR exhibiting an open channel probability (P_o) < 0.1 (10) that is inhibited by low affinity Mg²⁺-independent ATP binding to an unidentified site(s) (9). SUR increases the P_o of K_IR6.2 channels in the absence of nucleotides and decreases the apparent K_D for inhibitory ATP through separable interactions with the K_IR (10, 11). The activity of homomeric K_IR6.1 channels has not been demonstrated, and SUR is apparently required to stimulate channel activity.

The possible functional significance and even existence of hybrid (K_IR6.1/K_IR6.2)/SUR complexes is controversial. Although over-expression of K_IR6.1 in Xenopus oocytes reduced surface expression of K_IR6.2 lacking the RKR motif (2) indicating co-assembly, expression of a dominant negative K_IR6.1 construct with K_IR6.2 and SURs in A549 cells or in ventricular cardiomyocytes failed to provide evidence for heteromultimerization (12).

To determine the properties of hybrid channels, we generated K_IR6.X-X-X-X concatemers that assemble functional channels with SUR1. Analysis of these channels shows their conductivity is specified both by the ratio of K_IR6.1 to K_IR6.2 and by the subunit order. Unexpectedly, inclusion of one K_IR6.2 subunit was sufficient to produce spontaneous bursting in the absence of ATP, and all of the possible hybrid channels exhibited a uniform sensitivity to inhibitory ATP that was indistinguishable from K_IR6.2-2-2-2-based channels.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Molecular Biology-- Using oligonucleotide primers and standard PCR methods, we engineered two parental plasmids encoding human K_IR6.1 and human K_IR6.2 (in pECE) (13). A BglII site followed by an SGGGA linker was inserted before the ATG start codon, and a BamHI site followed by a GGGS linker was inserted at the 3'-end. The 5'-K_IR6.2 primer was 5'-GAGAAGATCTGGTGGAGGTGCCATGCTGTCCCGCAAGGGCATC-3'. The 3'-K_IR6.2 primer was 5'-TCTCGGATCCTCCACCGGACAGGGAATCTGGAGAGA-3'. The 5'-K_IR6.1 primer was 5'-GAGAAGATCTGGAGGCGGTGCCATGTTGGCCAGAAAGAGTAT-3'. The 3'-K_IR6.1 primer was 5'-TCTGGATCCTCCACCTGATTCCGATGTGTTTTGAT-3'. These parental cDNAs were used to construct a series of plasmids expressing concatenated K_IR6.X subunits. For example, a K_IR6.2-K_IR6.1 dimer was constructed by opening the K_IR6.2 parental plasmid with BamHI, treating the restricted DNA with calf intestinal alkaline phosphatase (Roche Molecular Biochemicals), and then subcloning in the BglII-BamHI fragment encoding K_IR6.1. The BglII (AGATCT) and BamHI (GGATCC) sites are compatible, producing two orientations; the correct orientation eliminates the restriction site and was established by restriction digests and/or by sequencing. Using these parental plasmids, it was possible to concatenate any combination of K_IR6.X subunits. In all cases, the resulting concatemeric protein begins with the correct methionine, has an eight-amino acid linker, GGGSGGGA, between each subunit and has additional four amino acids, GGGS, at the C terminus. Monomeric or concatenated K_IR were transfected with human SUR1 (13) and a green fluorescent protein marker into COSm6 cells.

Electrophysiology-- Cell culture, patch clamp recording, single-channel kinetics, and steady-state ATP inhibition analysis were done as described previously (14). The pipette solution contained (in mM): KCl, 145; MgCl₂, 1; CaCl₂, 1; HEPES, 10; pH 7.4 (KOH). The "intracellular" bath solution contained: KCl, 140; MgCl₂, 1; EGTA, 5; HEPES, 5; KOH, 10, pH 7.2. The [Mg²⁺]_i was kept at a quasi-cytosolic level of ~0.7 mM by adding MgCl₂ to account for the Mg²⁺ binding to nucleotides. The Mg²⁺-free internal solution contained (in mM): KCl, 140; EDTA, 5; HEPES, 5; KOH, 10, pH 7.2. Intracellular nucleotides and possible open channel blockers such as Na⁺ did not significantly affect the amplitude of the inwardly directed unitary K_IR current, i. A moderate density of reconstituted channels allowed measurement of i in the cell-attached configuration and determination of the mean NP_o, which was normalized to the maximal NP_o in the in-out configuration to provide an accurate measure of the relative activity of channels in the cell. The i value was determined from the difference between peaks of a multi-Gaussian fit to the all-points single-channel current amplitude histogram. In those cases in which channels spend either a very low or very high fraction of their time in long-lived intervals, intervals were added to obtain all-points i-histograms with comparable areas under the two peaks. The lack of subconductance state(s) resolvable at 2-5 kHz and 500 mV*pA¹ simplified the determination of i. The conductance, g, for each construct was determined by linear regression analysis of averaged I -V_m data points between 80 and 20 mV using the standard deviation as the statistical weight. The precision of the g values is ~0.1 picosiemens and is not limited by the digital resolution of i or the accuracy of the voltage V_m clamp (the junction potential was <1 mV). To correct g values for the effects of possible slow solution and/or temperature changes we normalized g for each construct to the g value of K_IR6.2-2-2-2/SUR₄ channels tested in parallel. Differences in averaged values (mean ± S.D.) with p < 0.05 (unpaired Student's t test) were considered significant. In Fig. 7, the horizontal dotted lines show the zero-K_ATP channel current level; downward deflections correspond to the inward current direction, isolation of inside-out patches is marked by i-o at the vertical arrows, and error bars show ±S.D.

	RESULTS

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Co-expression of the parental K_IR6.1_GGGS and K_IR6.2_GGGS constructs with SUR1 produced channels that were indistinguishable from native, and recombinant K_NDP and K_ATP channels in terms of their nucleotide responsiveness and an ~2-fold difference in their g values (Fig. 1A). K_NDP channels were active in cell-attached patches, and the transition to a nucleotide-free intracellular solution in the inside-out configuration resulted in a transient increase in their activity before they closed. These K_NDP channels remained in an operational state and could be activated by MgUDP, known to be an effective stimulator but a poor inhibitor of K_IR6.2/SUR1 channels (15), which does not reactivate run-down channels like MgATP (16)). The rapid wash-out of ATP applied in the presence of Mg²⁺ resulted in a transient increase in K_NDP channel activity similar to that observed upon transition to the inside-out configuration. By contrast, the spontaneous steady-state activity of K_IR6.2/SUR1 channels in an inside-out patch was dramatically reduced by sub-millimolar MgATP and inhibited by ATP in Mg²⁺-free internal solution with an IC_50(ATP) of 6.1 ± 0.4 µM (n = 5, not shown). This value was indistinguishable from that of wild type -cell K_ATP channels determined under similar conditions (10, 11), verifying that there is no effect of the GGGS tail on ATP-inhibitory gating.

View larger version (31K): [in this window] [in a new window]   Fig. 1.   Properties of "classical" versus hybrid-6.X4/SUR14channels. A, a, responses of KIR6.1GGGS/SUR1 (upper trace) and KIR6.2GGGS/SUR1 (lower trace) channels to rapid changes in nucleotides at the inner face of a membrane patch held at 40 mV. The break in the upper trace is ~1 min. b, comparison of g of KIR6.1 (upper trace and I-Vm relationship)-containing versus KIR6.2 (lower trace and I-Vm relationship)-containing channels in the solutions used in a. The best fit to a linear function (dashed line) gives a g value of 34.2 and 68.1 picosiemens for KIR6.1- and KIR6.2-based channels, respectively. The 95% confidence limits are given by the dotted lines (n = 4 for each channel). B, a, KIR6.2-2-2-2/SUR1 (top) and KIR6.1-1-1-2/SUR1 (bottom) channel currents recorded at 60 mV under the conditions used in A except for the Mg2+-free internal solution with ATP. b, ATP dose responses with fitted pseudo-Hill inhibitory curves (IC50(ATP) = 17.9 µM and h = 1.25 for the dotted line versus IC50(ATP) = 14.4 µM and h = 1.49 for the solid line) and the i histograms for the KIR6.2-2-2-2/SUR1 and KIR6.1-1-1-2/SUR1 channels observed in a. Here and in C, KIR6.1, KIR6.2, and SUR1 are shown as white, black, and gray circles, respectively. C, summary of the relative g and IC50(ATP) determinations for different hybrid channels. The relative g values are different (p < 0.05), whereas the IC50(ATP) values are not (even at p = 0.1). The h values for the best-fit ATP-inhibitory curves varied between 1.23 and 1.49; n = 3-5. The IC50(ATP) for KIR6.2-2-2-2/SUR1 channels was 14.2 ± 2.4 µM (h = 1.3; n = 19).

On the basis of the different characteristics of the parental channels, we expected hybrid channels to have intermediate properties, and we determined g, ability to burst spontaneously, and ATP sensitivity of K_IR6.X-X-X-X concatemers co-expressed with SUR1. Co-expression of K_IR6.2-2-2-2 with SUR1, but not the concatemer alone, generated spontaneously active channels, which were inhibited by ATP with an IC_50(ATP) ~10⁵ M (Fig. 1B), verifying that linking the pore forming subunits did not compromise inhibitory nucleotide binding. Co-expression of K_IR6.1-1-1-1 with SUR1 generated channels with negligible activity in nucleotide- and/or Mg²⁺-free internal solutions that were maximally activated by 10 mM MgUDP. Finally, co-expression of each K_IR6.1-X-X-2 with SUR1 generated nucleotide-sensitive K⁺ channels. As illustrated in Fig. 1B, K_IR6.1-1-1-2/SUR1 channels produced currents after wash-out of UDP and Mg²⁺, which were half-maximally inhibited by ~10⁵ M ATP. To support the assertion that these currents were through hybrid pores and not through K_IR6.2₄ pores assembled from multiple concatemers, we collected first-level openings from records of multi-channel currents partially inhibited by ATP over a time interval sufficient to accumulate a statistically significant number of single-channel openings. Segments of the resulting traces for K_IR6.1-1-1-2 versus K_IR6.2-2-2-2-containing channels are shown to the right in Fig. 1Ba. The all-points current amplitude histograms constructed from these traces (Fig. 1Bb, right) revealed a single i peak corresponding to a g intermediate between that of K_IR6.1₄ and K_IR6.2₄ pores. The uniform intermediate, g, was derived from a similar test with millimolar MgATP, which will maintain low P_o openings of channels with any K_IR composition. The results illustrate the homogeneity of these hybrid channels and demonstrate that one K_IR6.2/tetrameric pore is sufficient to ensure spontaneous bursting and confer classical K_ATP channel-like sensitivity to inhibitory ATP. Similar measurements on all of the other channels generated by co-expression of K_IR6.1-2-1-2, K_IR6.1-1-2-2, or K_IR6.1-2-2-2 with SUR1 (3-5 independent transfections for each combination with >10³ channels observed) led to the conclusion that each concatemer specified one hybrid channel type in which characteristics were determined uniquely by concatemer composition. This finding permitted determination of statistically representative values of relative g versus IC_50(ATP) for all possible types of spontaneously bursting hybrid K_ATP channels in Mg²⁺-free internal solution (Fig. 1C). The results show four types of channels with distinguishable intermediate g values, consistent with the concatemers specifying subunit composition and order in tetrameric pores. Two K_IR6.1 subunits reduce the conductivity more when they are "across the pore" than when they are adjacent to each other, consistent with observations in K_V channels (17). In contrast to the differences in g, the IC_50(ATP) values are statistically indistinguishable, and we conclude that all of the hybrid K_IR6.X-X-X-X/SUR₄ channels are as highly sensitive to inhibitory ATP as K_IR6.2-2-2-2/SUR₄ channels.

	DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Although the existence of true hybrid K_IR6.1/K_IR6.2 channels is problematic (see (Refs. 2 and 12), our results show that concatemerized subunits form functional, regulated, hybrid K_ATP channels when co-expressed with SUR1, demonstrating that the interactions involved in gating are preserved. The characteristics of these hybrid channels are determined by the K_IR6.1/K_IR6.2 ratio and subunit position in the concatemers consistent with a single concatemer forming a pore. The results imply that a search for hybrid K_ATP channels in native cells is reasonable and that measurements of i and IC_50(ATP) from the same single channel patch will allow verification of the K_IR composition of these presumably rare K_IR/SUR channels in mammalian cells.

The different hybrid channels exhibit distinguishable intermediate g values, although the H5 regions of K_IR6.1 and K_IR6.2 are identical. Our results are in agreement with the report by Repunte et al. (5) that amino acids in the M1-H5 loop or "turret" (positions 123-125 and 113-115 for K_IR6.1 and K_IR6.2, respectively) and in the H5-M2 loop (position 148 and 138 for K_IR6.1 and K_IR6.2, respectively) specify the difference in g between K_IR6.1- and K_IR6.2-based channels. Hybrid pores containing greater numbers of K_IR6.2 extracellular loops have higher g values. The result is consistent with the smaller volume of the amino acid side chain of Val¹³⁸ versus Met¹⁴⁸ in K_IR6.2 versus K_IR6.1. We see a positional effect of adjacent versus diagonal extracellular loops on g, which could be the result of limiting diffusion of K⁺ through the outer vestibule of the pore and/or from nonequivalent interactions between the different K_IR6.X subunits affecting the molecular dynamics of the K⁺ selectivity filter. The first possibility is supported by a prediction from a K_IR6.2 tetramer model (5) based on the KcsA crystal structure (18) that two Met¹⁴⁸ side chains of K_IR6.1 will restrict the diffusion of K⁺ through the external vestibule more than the less bulky Val¹³⁸ side chain of K_IR6.2 when they are across the pore rather than adjacent to each other. A similar idea, based on the hydrodynamic theory of Dwyer et al. (19), has been used to explain a qualitatively similar effect of subunit order on g of heteromeric cyclic nucleotide-gated channels (20). With regard to possible effects on the dynamics of the selectivity filter, we note that the potential intersubunit salt bridges between the conserved R and E following the K⁺ channel signature G(Y/F)G sequence are unlikely as pK_A calculations, based on a homology model of the K_IR6.2 tetramer embedded into a lipid bilayer (21), indicate that these E are protonated. Intersubunit H-bonds equivalent to those between Trp⁶⁸ in the pore helix and Tyr⁷⁸ in the signature motif of adjacent subunits in KcsA (22) are also unlikely because phenylalanines occupy the corresponding positions in K_IR6.X. We note, however, that Glu¹⁰⁴ and Glu¹⁰⁸, at the extracellular mouth of the K_IR6.2 tetramer (21), are in the variable M1-H5 turret region of K_IR6.X. Repunte et al. (5) have suggested that this region does not contribute to the g difference, but possible differential interactions between adjacent residues in K_IR6.1 and K_IR6.2 might result from the longer extracellular linker in K_IR6.1 and contribute to the effects of subunit order on g. Molecular dynamics simulations of hybrid K_ATP channels may aid our understanding of the possible biophysical mechanisms behind the observed conductivity differences in K_IR6.X₄ hybrids that result from the asymmetrical contributions of subunits to the permeation properties of heteromultimeric K_IR (23).

The substitution of one K_IR6.2 into a K_IR6.1-6.1-6.1-6.1 concatemer was sufficient to destabilize the permanently closed state of K_NDP channels seen in the absence of Mg²⁺- and nucleotide-dependent stimulation by SUR1. This gain-of-function, spontaneous opening of K_IR6.1-containing channels allowed determination of the ATP sensitivity of hybrid K_IR in the absence of the magnesium nucleotides required to open K_IR6.1/SUR channels. The IC_50(ATP) values for hybrid channels were indistinguishable from the ~10⁵ M value for K_IR6.2-2-2-2/SUR1₄ channels. One interpretation of these results is consistent with the idea that K_IR6.1 does not interact with inhibitory nucleotides (7), in which case occupation of the cytoplasmic domain(s) of one K_IR6.2 stabilizes the closed pore as strongly as occupation of four domains. However, this interpretation is in poor agreement with the differences in the ATP dose response observed for K_ATP channels with different numbers of K_IR6.2 subunits with C-terminal mutations (our preliminary data² and the preliminary report of Li et al. (31)). An alternative interpretation, that K_IR6.1 has a low affinity inhibitory ATP binding site(s) similar to K_IR6.2, is consistent with the fact that the C-terminal residues of K_IR6.2 in which mutation produces the most dramatic increases in the IC_50(ATP) for K_ATP channels, i.e. the double mutant Arg⁵⁰/Lys¹⁸⁵ (24), Ile¹⁸², and Gly³³⁴ (25) are conserved in K_IR6.1. Moreover, the transient increases in K_NDP channel currents induced by rapid wash-out of MgATP in conventional patches with "fast" diffusion access (Fig. 1Aa) provide semiquantitative evidence that the K_IR6.1 tetramer is as sensitive to inhibitory ATP as the K_IR6.2 tetramer assembled with the same SUR. We interpret this transient response as follows. During its application, millimolar MgATP binds to both SUR1 and K_IR6.X. Nucleotide-bound SUR1 stimulates K_IR6.1/SUR1 more efficiently than K_IR6.2/SUR1 channels, thus better masking the inhibitory action of ATP on the K_NDP channels (Fig. 1Aa). Upon nucleotide removal, unbinding of nucleotide(s) from the low affinity inhibitory ATP site(s) on the K_IR produces a quasi-sigmoidal rise in current, which can be resolved if nucleotide unbinding is not limited by its "desorption" (26) (departure) from the cytoplasmic surface of the patch. This kinetic phenomenon can be resolved best in conventional "flat" patches by rapid solution exchange but not in "invaginated" macro-patches with solution exchange times of >10 ms. In parallel, but independently, a slower relaxation of the magnesium-nucleotide-activated K_IR/SUR complex, due to nucleotide unbinding from SUR (upon or independently of ATP-hydrolysis), results in decay of channel activity. The observed <10² ratio of the mean NP_o of K_NDP channels at quasi-cytosolic [Mg-ATP] to the NP_o during the transient peak after wash-out suggests a submillimolar IC_50(ATP) for K_NDP channels. If we assume there is a common mechanism coupling inhibitory ligand binding to closure of the M2 bundle, the postulated "inner gate" of K_IR (15, 27, 28) based on the proposed function of this bundle in KcsA channels (18, 29, 30), then the uniform IC_50(ATP) hybrid channel values are a reflection of similar low affinity ATP binding loci in both K_IR6.1 and K_IR6.2 in which the K_D for inhibitory ATP binding is decreased by SUR (10, 11). Validation of this hypothesis will require direct comparison of ATP binding to purified K_IR6.1 and K_IR6.2 in the presence of versus absence of SUR and determination of ATP dose responses of K_IR6.1₄-based channels.

	ACKNOWLEDGEMENTS

We thank Li-Zhen Song for excellent technical assistance with cell culture and transfections.

	FOOTNOTES

^* The work was supported by grants from the American Heart Association (to A. P. B.) and the National Institutes of Health (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: 713-790-0545; E-mail: ababenko@bcm.tmc.edu.

Published, JBC Papers in Press, August 23, 2000, DOI 10.1074/jbc.C000553200

² A. P. Babenko, unpublished data.

	ABBREVIATIONS

The abbreviations used are: SUR, sulfonylurea receptor; g, unitary conductance; IC_50(ATP), IC₅₀ value for ATP; K_NDP, nucleotide-diphosphate-activated K_ATP channels; P_o, mean open channel probability.

	REFERENCES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

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This Article Abstract Full Text (PDF) All Versions of this Article: 275/41/31563    most recent C000553200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Babenko, A. P. Articles by Bryan, J. Search for Related Content PubMed PubMed Citation Articles by Babenko, A. P. Articles by Bryan, J. Social Bookmarking                      What's this?