Department of Biology, Georgia State University, Atlanta, Georgia 30302-4010
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ABSTRACT |
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Kir1.1 (ROMK1) is inhibited by hypercapnia and intracellular acidosis with midpoint pH for channel inhibition (pKa) of ~6.7. Another close relative, Kir4.1 (BIR10), is also pH sensitive with much lower pH sensitivity (pKa ~6.0), although it shares a high sequence homology with Kir1.1. To find the molecular determinants for the distinct pH sensitivity, we studied the structure-functional relationship using site-directed mutagenesis. An NH2-terminal residue (Lys-53) was found to be responsible for the low pH sensitivity in Kir4.1. Mutation of this lysine to valine (K53V), a residue seen at the same position in Kir1.1, markedly increased channel sensitivity to CO2/pH. Reverse mutation on Kir1.1 (V66K) decreased the CO2/pH sensitivities. Interestingly, mutation of these residues to glutamate greatly enhanced the pH sensitivity in both channels. Other contributors to the distinct pH sensitivity were histidine residues in the COOH terminus, whose numbers are fewer in Kir4.1 than Kir1.1. Mutation of two of these histidine residues in Kir1.1 (H342Q/H354N) reduced CO2/pH sensitivities, whereas the creation of two histidines (S328H/G340H) in Kir4.1 increased the CO2/pH sensitivities. Combined mutations of the lysine and histidine residues in Kir4.1 (K53V/S328H/G340H) gave rise to a channel that had CO2/pH sensitivities almost identical to those of the wild-type Kir1.1. Thus the residues demonstrated in our current studies are likely the molecular basis for the distinct pH sensitivity between Kir1.1 and Kir4.1.
ion channel; hypercapnia; gene expression; patch clamp; chemoreception
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INTRODUCTION |
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INWARD RECTIFIER POTASSIUM CHANNELS (Kir) play important roles in cellular excitability. Activity of these channels is modulated by various intra- and extracellular substances (11). One of these modulators is a proton that causes inhibition of Kir1 (ROMK), Kir2.3 (HIR), and Kir4.1 (BIR10) (5, 6, 9, 19, 24). The pH sensitivity of Kir1 seems to play a key role in the maintenance of pH and K+ homeostases by renal epithelial cells (6, 9, 19), while the pH-sensitive Kir4.1 may be a potential molecule for CO2 chemoreception in respiratory neurons (21, 22). The Kir1.1 and Kir4.1 share 47% identity and ~75% homology in their amino acid sequences (2, 8). Like other Kir channels, both Kir1.1 and Kir4.1 channels appear to be tetramers with two transmembrane domains (M1 and M2) linked by a pore-forming loop (P or H5 region) containing a signature GYG motif for K+ channels. Kir1.1 and Kir4.1 also have a Walker-A motif in the COOH terminus, suggesting a potential regulation by ATP. On the basis of many such shared features in Kir1 and Kir4, it has been argued that these two channels should be grouped into one subfamily of Kir channels (12, 15, 18).
Although Kir4.1 and ROMK1 have a number of similarities, intracellular pH (pHi) sensitivity of Kir1.1 is much higher (midpoint pH for channel inhibition pKa ~6.7) than that of Kir4.1 (pKa ~6.0). We believe that this difference renders these two channels an optimal pair of subjects for studying structure-functional relationship of Kir channels, since it is possible that the difference is due to small variations in amino acid sequences and their tertiary structures. More importantly, demonstration of molecular determinants for the distinct pH sensitivity may lead to a discovery of novel amino acid residues as well as molecular motifs responsible for channel activity control. Therefore, we designed these experiments in which mutation analyses were carried out on Kir1 and Kir4 using site-directed mutagenesis combined with patch clamp. Our results showed that multiple residues were involved in proton sensing in these Kir channels.
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METHODS |
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Construction of mutants. Kir1.1 (GenBank accession no. X72341) and Kir4.1 (GenBank accession no. X83585) cDNAs were generously provided by Drs. Steven Hebert and John Adelman, respectively (2, 8). These cDNAs were inserted into a eukaryotic expression vector, pcDNA3.1 (Invitrogen, Carlsbad, CA). Site-specific mutations were made using a site-directed mutagenesis kit (Stratagene, La Jolla, CA). Briefly, site-specific mutations were generated using a pair of mutation-containing primers and the Pfu DNA polymerase-based polymerase chain reaction. The mutant DNAs were further amplified in the XL1 strain of Escherichia coli and purified. Correct mutations were confirmed with DNA sequencing. Wild-type (WT) and mutant Kir channels were subsequently expressed in Xenopus laevis oocytes.
Preparation and injection of Xenopus oocytes. Oocytes were surgically removed from adult frog (Xenopus laevis) and treated with 2 mg/ml collagenase (type I, Sigma Chemical, St. Louis, MO) in the OR2 solution containing (in mM) 82 NaCl, 2 KCl, 1 MgCl2, and 5 HEPES for 90 min at room temperature (~25°C) and pH 7.4. After three washes with the OR2 solution, cDNA in the pcDNA3.1 vector (40-50 ng in 50 nl of double-distilled water) was injected into the oocytes. The oocytes were then incubated at 18°C in the ND-96 solution containing (in mM) 96 NaCl, 2 KCl, 1 MgCl2, 1.8 CaCl2, 5 HEPES, and 2.5 sodium pyruvate plus 100 mg/l geneticin (pH 7.4).
CO2 exposure and intracellular acidification. Xenopus oocytes were placed in a semi-closed recording chamber (Medical System, Greenvale, NY), where perfusion solution bathed both the top and bottom surfaces of the oocytes. The perfusate and the superfusion gas entered the chamber from the inlet at one end and flowed out at the other end. On the top cover of the chamber there was a 3 × 15-mm gap that served as the gas outlet and provided access to the oocytes for recording microelectrodes. The perfusate (KD 90) contained (in mM) 90 KCl, 3 MgCl2, and 5 HEPES (pH 7.4). At baseline, the chamber was ventilated with atmospheric air. Exposure of the oocytes to CO2 was carried out by switching the superfusion air to a gas mixture containing 15% CO2-21% O2-balance N2. The high solubility of CO2 resulted in a detectable change in intra- or extracellular pH as fast as 10 s in these oocytes.
Electrophysiology.
Whole cell currents were studied on the oocytes 2-4 days after
injection as we described previously (21, 24). In brief, two-electrode voltage clamp was performed using an amplifier (Geneclamp 500; Axon Instruments, Foster City, CA) at room temperature
(~25°C). The extracellular solution contained (in mM) 90 KCl, 3 MgCl2, and 5 HEPES (pH 7.4). Cells were impaled with the
use of electrodes filled with 3 M KCl (0.3-0.6 M). Patch-clamp
experiments were performed using fire-polished borosilicate glass
pipettes. The oocyte vitelline membranes were mechanically removed
after exposure to hypertonic solution (400 mosM) for 5 min. The
stripped oocytes were placed in FVPP solution [in mM: 40 KCl, 75 potassium gluconate, 5 potassium fluoride, 0.1 sodium vanadate, 10 potassium pyrophosphate, 1 EGTA, 0.2 ADP, 10 PIPES or HEPES, 10 glucose, and 0.1 spermine (pH 7.4)]. Macroscopic current recordings
were performed on a giant inside-out patch preparation by using
recording pipettes of 0.5-2.0 M
(22, 23). The same
FVPP solution containing ~150 mM K+ was applied to both
sides of membranes. In a control experiment, we found that macroscopic
currents recorded from giant inside-out patches showed <10% reduction
over a 20-min period of recordings in the FVPP solution. Current
records were low-pass filtered (2,000 Hz, Bessel, 4-pole filter,
3
dB), digitized (10 kHz, 12-bit resolution), and stored on computer disk
for later analyses (pCLAMP 6; Axon Instruments). Nullification of
junction potentials between bath and pipette solutions was routinely
attempted before seal formation. A parallel perfusion system was used
to administer agents to patches at a rate of ~1 ml/min with no dead
space (22, 23). Low pH exposures were carried out by using
the FVPP solution that had been titrated to various pH levels as
required by experimental protocols. HEPES and PIPES buffers were used
in these experiments because of their appropriate buffering ranges and
membrane impermeability (14).
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RESULTS |
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Distinct CO2 and pH sensitivities exist between Kir1.1
and Kir4.1.
Whole cell currents were studied in Xenopus oocytes that had
received an injection of Kir1.1, Kir4.1, or one of their mutant cDNAs.
In the two-electrode voltage-clamp mode, inward rectifying currents as
large as 20 µA were observed in most injected oocytes. These currents
were sensitive to micromolar concentrations of Ba2+ and
Cs+ (21, 24). Both Kir1.1 and Kir4.1 currents
showed evident rectification (Fig. 1,
A and B). Exposure of the oocytes to
CO2 (5, 10, and 15%) for 5-8 min produced a
reversible and concentration-dependent inhibition of these inwardly
rectifying currents (Fig. 1). With 15% CO2, 70.1 ± 4.0 (n = 8) and 23.7 ± 5.6 (n = 6) of the whole cell currents were inhibited in WT Kir1.1 and Kir4.1,
respectively. These inhibitions did not show evident voltage dependence
in a voltage range from 160 to 100 mV (21, 24). The
inhibition of Kir1.1 and Kir4.1 currents by CO2 was
mediated by a decrease in pHi, since selectively lowering
pHi but not extracellular pH (pHo) to the
corresponding pH levels (pHi 6.6, pHo 6.2)
observed during the 15% CO2 exposure inhibited both
currents to the same degree as hypercapnia did. Macroscopic currents
recorded in excised inside-out patches were similarly inhibited (Fig.
2). The pHi sensitivity of
Kir1.1 (pKa ~6.73, h = 3.6),
however, is much higher than that of Kir4.1 (pKa
5.98, h = 2.4) (Fig. 2C and Table
1).
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Mutation of Lys-67 in Kir4.1 interrupts CO2/pH
sensitivities.
Previous studies have shown that Lys-80 in Kir1.1 is critical for pH
sensing. Mutation of the Lys-80 into methionine completely eliminates
channel sensitivity to pHi (7). This lysine
residue close to the M1 region has therefore been proposed to be a pH sensor in Kir1 channels. In Kir4.1, a lysine (Lys-67) is also found at
the same position. We have previously shown that mutation of Lys-67 to
methionine, a residue found at the same position in Kir2.1, largely
eliminates channel sensitivities to 15% CO2 and
pHi (21). To further understand this lysine
residue in proton sensing, we systematically mutated it to histidine,
glutamate, and glutamine as well as methionine (Fig.
3). Although CO2 sensitivity was lost in K67Q and K67E mutants, the K67H-mutant Kir4.1 was still
modestly sensitive to 15% CO2 (13.1 ± 2.0, n = 5). Because this lysine exists in both Kir1.1 and
Kir4.1, the difference in their pH sensitivities should depend on other
residues.
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Lower pH sensitivity in Kir4.1 is related to Lys-53.
Thr-51 in Kir1.2 is known to play a role in modulating the pH
sensitivity (4). Since this residue is conserved in both Kir1.1 (Thr-70) and Kir4.1 (Thr-57), it should not be responsible for
the distinct pH sensitivity in these two channels. To determine the
role of the NH2 terminus in pH sensing, we examined the
amino acids around this threonine residue. Sequence alignment of
positions 64-83 in Kir1.1 and positions 50-69 in Kir4.1 show
that two residues clearly contrast their counterparts in the other
channel, i.e., Lys-53 and Gln-63 in Kir4.1 vs. Val-66 and Lys-76 in
Kir1.1. Mutation of Lys-53 to valine in Kir4.1 (K53V) significantly
increased the channel sensitivity to CO2 (Fig. 3) and
pHi (Fig. 4). The
pKa value of the K53V-mutant Kir4.1 became pH
6.58, which is very close to that of Kir1.1 (pKa
6.73) (Fig. 5 and Table 1). Subsequently, we reversed the mutation on the Val-66 in Kir1.1. The V66K mutant had a
much lower CO2 sensitivity (20% inhibition by 15%
CO2) than the WT Kir1.1. Recordings from excised patches
showed that for this mutant, pKa = 6.07 and
h = 3.2 (Figs. 4 and 5). Thus the V66K-mutant Kir1.1
turned more like Kir4.1 than Kir1.1 in terms of its pH/CO2
sensitivities. In contrast, the Q63K-mutant Kir4.1 showed
CO2 sensitivity (30% inhibition by 15% CO2)
still similar to that of the WT Kir4.1, suggesting that residue Gln-63
does not play a key role in the different pH sensitivity of these
channels.
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Histidine residues in the COOH terminus are involved in pH sensing
in both Kir1.1 and Kir4.1.
Although the increase in pKa value in the
K53V-mutant Kir4.1 may have provided some explanations for the lower pH
sensitivity of Kir4.1 than Kir1.1, the h values of the WT
and K53V-mutant Kir4.1 remained significantly low compared with those
of the WT and V66K-mutant Kir1.1 (P < 0.001). One
possibility is that Kir1.1 has more proton-binding sites than Kir4.1
does, an idea supported by our previous studies showing that multiple
histidines in the COOH terminus are involved in proton sensing in
Kir1.1, mutations of which cause decreases of both
pKa and h (3). Thus we
studied the histidine residues in the Kir1.1 and Kir4.1
proteins. There are six histidines in the COOH terminus of
Kir1.1, but four in that of Kir4.1. To test the hypothesis that Kir1.1
has more proton-binding sites than Kir4.1 in physiological pH range, we
created two histidines in Kir4.1 at positions 328 and 340, corresponding to H342 and H354 in Kir1.1. Creation of these histidine
residues (S328H/G340H) greatly increased the CO2
sensitivity of mutant Kir4.1 (Fig. 3). In the S328H/G340H Kir4.1, the
titration curve shifted by ~0.5 pH units rightward to a
pKa of 6.50 (P < 0.001) with a
significant increase in h value (P < 0.05)
(Figs. 6 and
7; Table 1). When two
histidines were mutated to nontitratable residues in Kir1.1 (H342Q/H354N), the pH sensitivity of Kir1.1 changed in exactly the
opposite direction (pKa = 6.39 and
h = 3.0; P < 0.001 and P < 0.05, respectively). These results are thus
consistent with the idea that histidine residues in the COOH terminus
of these Kir channels are likely to be proton-binding sites. In an
attempt to locate the proton-binding sites in the WT Kir4.1, we studied all histidine residues on the COOH and NH2 termini of
Kir4.1, in which histidines were mutated into nontitratable alanine or glutamine either individually or jointly. While H257Q and H184Q/H190A mutations resulted in nonfunctional channels, all expressed mutants (H221Q, H184Q, and H43A) showed CO2 sensitivity
indistinguishable from that of the WT Kir4.1 (Fig. 3), suggesting that
proton-binding sites may be located in either His-190 or His-257 or in
other residues titratable at near physiological pH (3, 5,
10).
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Potential interactions of multiple residues in pH sensing. Our results have indicated that multiple sites are involved in pH sensing in these Kir channels. We noticed that either the K53V mutant or the creation of histidine residues in the COOH terminus alone yielded mutant Kir4.1 that still showed lower pKa and h values than the WT Kir1.1 did. Thereafter, combined mutations of all these three residues were constructed. The mutant Kir4.1 (K53V/S328H/G340H) had a pH sensitivity very close to that of WT Kir1.1 with a pKa of 6.78, and the h value (3.0) shifted to a level between that of WT Kir1.1 and WT Kir4.1 (Fig. 7). Combined mutations of some of these residues with Lys-67 in Kir4.1 (K53V/K67M, K67M/S328H/G340H) still showed a low CO2 sensitivity identical to that of the K67M mutant (Fig. 3). Therefore, the presence of the Val-66 in the NH2 terminus and additional titratable histidines in the COOH terminus appears to enable higher proton sensitivity in Kir1.1 than in Kir4.1.
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DISCUSSION |
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Fakler et al. (7) identified a lysine residue close to the M1 in Kir1.1 that is critical for pH sensing in the ROMK1/ROMK2 channel. Mutation of the Lys-80 to methionine completely eliminates the pH sensitivity. Reverse mutation in Kir2.1 introduces the pH sensitivity to the mutant channel (7). At the same position, a lysine residue is also found in Kir4.1. As expected, we found that the K67M- and K67Q-mutant Kir4.1 lost their pH sensitivity. The similar effect of lysine mutation on Kir1.1 and Kir4.1 indicates that this lysine residue is not responsible for the distinct pH sensitivity, though it is involved in certain common processes in channel sensitivity to intracellular protons in both channels.
Previous studies have suggested that a cytoplasmic region in the NH2 terminus contained a molecular motif modulating the pH sensitivity of ROMK2 (4). This region is known as the "Q" region, which was originally believed to be semi-transmembrane and was later proved to be cytoplasmic. A threonine residue (Thr-51) in this region is critical for pH sensitivity in ROMK2. Mutation of this residue to alkaline residue lowers pH sensitivity, whereas replacing it with acidic residue enhances channel sensitivity to pHi (4). Since this threonine is conserved in both Kir1.1 and Kir4.1, it should not be the determinant for the distinct pH sensitivity in these channels. Unlike the threonine residue, an adjacent site is not conserved. Indeed, we have found that this site is one of the determinants for the distinct pH sensitivity between these channels. By mutual mutating lysine and valine at this position, we have found that the K53V-mutant Kir4.1 resembles the WT Kir1.1, and the V66K-mutant Kir1.1 appears more like the WT Kir4.1, in terms of pH sensitivity. Hydrophobicity at this site is not critical since the enhanced pH sensitivity remains after mutations to neutral nonpolar (Val) and neutral polar (Gln) residues. Interestingly, a glutamine is found at the same position in Kir4.2 (12). Our results thereby anticipate a higher pH sensitivity in Kir4.2 than in Kir4.1, although the pKa value in the Kir4.2 is still not measured. Whereas the low pH sensitivity is retained only in the K53R-mutant Kir4.1, substitution of the Lys-53 with an acidic amino acid (Glu) enhances pH sensitivity more strongly than the K53V mutant, suggesting that the status of electrical charge rather than the species of amino acids at this site plays a role in pH sensing of these Kir channels. This suggestion is further supported by our results from mutations on Val-66 in Kir1.1. High pKa value in the Kir1.1 is lost in the V66K mutant but maintained in V66N. Similarly to the K53E-mutant Kir4.1, the V66E mutant shows the highest pH sensitivity.
It is possible that the charged residue interacts with pH sensor(s) and shifts the apparent pK of the sensor or alters the local pH around the sensor by ionic interaction with protons, as suggested by Choe et al. (4). Another potential mechanism that can explain these observations is that positive charges in this region create a repulsive force against other channel domains that may interact with this region and become positively charged at low pH. Apparently, the COOH terminus with several titratable histidine residues is likely to be the counterpart of the interaction. Additionally, both K53E-mutant Kir4.1 and V66E-mutant Kir1.1 show relatively low h values, suggesting that negative charges may increase the attracting force to the COOH-terminal domain so that the NH2-COOH interaction occurs even before all essential titratable residues in the COOH terminus are protonated.
By introducing potentially titratable histidine residues into Kir4.1 to sites at which potential proton-binding residues are identified in Kir1.1 (3), we have successfully increased the pKa level in the S328H/G340H-mutant Kir4.1 and somewhat increased the h value. Moreover, we have found that removal of two histidine residues in Kir1.1 reduces its pH sensitivity, consistent with our previous observations (3). Thus it is likely that the presence of more proton-binding sites in the Kir1.1 contributes to a high pH sensitivity in this channel. Whether there are proton-binding sites other than Lys-67 in Kir4.1 is unclear. On the basis of our data, nonconserved His-221, His-184, and His-43 all contribute little or nothing to the pH sensing. His-190 and His-257 may be the potential candidates. However, mutations of these histidines did not yield functional Kir4.1 channels.
Theoretically, titratable amino acids all can be protonated at certain pH levels if they are fully exposed in the protein tertiary structures. While some of the proton bindings are coupled to the modulation of channel activity, some are linked to other types of channel modulations such as rectification and ligand bindings (1, 9). Hence, multiple proton-binding sites may exist, although the proton bindings may be null given their ability to change channel activity in most cases. Protonation of a single site may cause a great change in channel activity only if this residue is located at a critical area. Otherwise, joint protonations may lead to a significant change in channel activity, as we have shown previously for histidine residues in the COOH terminus of Kir1.1 (3).
Protonation of Lys-80 residue in Kir1.1 has been suggested (7, 16). Since the pKa value of lysine is 10.78, titration of such a residue requires its interactions with other protein domains (7, 16). Studies have recently shown that the intercellular NH2 and COOH termini may interact under certain circumstances: both NH2 and COOH termini are required for gating of Kir channels by protons (14, 16, 17); the intracellular NH2- and COOH-terminal domains can bind each other in purified NH2 and COOH peptides (13, 20). It is possible that protonation of histidine residues in the COOH terminus conveys the COOH terminus to a conformation that can interact with the NH2-terminal domain near to Val-66 and Thr-70 in Kir1.1 (or the VT domain). The NH2-COOH interaction subsequently causes a change in the pKa value of Lys-80 or a conformational change of the M1 sequence through the Lys-80 residue, leading to a closure of the Kir channel. Since there are fewer titratable residues in the COOH terminus and a positive charge in the NH2-terminal domain of Kir4.1, its NH2-COOH domains may interact poorly, and thus this channel is less sensitive to intracellular acidosis than Kir1.1.
In conclusion, we have demonstrated several molecular determinants for the distinct pH sensitivity in Kir1.1 and Kir4.1. The presence of a lysine (Lys-53) and the lack of two histidine residues in Kir4.1 appear to render the channel lower in pH sensitivity than Kir1.1.
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ACKNOWLEDGEMENTS |
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We thank Drs. John Adelman and Steven Hebert for generosity in sharing the Kir4.1 and Kir1.1 cDNAs.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grant RO1 HL-58410 and American Heart Association Grant-in-Aid 9950528N.
Address for reprint requests and other correspondence: C. Jiang, Dept. of Biology, Georgia State Univ., 24 Peachtree Central Ave., Atlanta, GA 30303-4010 (E-mail: cjiang{at}gsu.edu).
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.
Received 9 June 2000; accepted in final form 20 June 2000.
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