ABCMdb

ABCC8 p.Lys1384Met

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Publications

PMID: 10674713 [PubMed] Fujita A et al: "Molecular aspects of ATP-sensitive K+ channels in the cardiovascular system and K+ channel openers."

No. Sentence Comment

565 Gribble et al. (1997b) found that the ATPi sensitivity of the SUR1/Kir6.2 channel was not modified by mutations on either or both of the two conserved lysine residues in the Walker A motifs in the first or the second NBF of SUR1 (K719A and K1384M, respectively). Login to comment
629 Gribble et al. (1997b) showed that either the K719A or K1384M mutation of r-SUR1 abolished the stimulatory effects of ADPi on the partial rundown SUR1/Kir6.2 channel, both in the presence and in the absence of ATPi. Login to comment
569 Gribble et al. (1997b) found that the ATPi sensitivity of the SUR1/Kir6.2 channel was not modified by mutations on either or both of the two conserved lysine residues in the Walker A motifs in the first or the second NBF of SUR1 (K719A and K1384M, respectively). Login to comment
633 Gribble et al. (1997b) showed that either the K719A or K1384M mutation of r-SUR1 abolished the stimulatory effects of ADPi on the partial rundown SUR1/Kir6.2 channel, both in the presence and in the absence of ATPi. Login to comment

PMID: 9382893 [PubMed] Shyng S et al: "Regulation of KATP channel activity by diazoxide and MgADP. Distinct functions of the two nucleotide binding folds of the sulfonylurea receptor."

No. Sentence Comment

139 Gribble et al. (1997) have recently shown that mutation of the conserved lysine residues in the Walker A motifs of either NBF1 (mutation K719A) or NBF2 (mutation K1384M), which are predicted to reduce ATP hydrolytic activity (Azzaria et al., 1989; Carson et al., 1995; Ko and Pedersen, 1995), can block the stimulatory effect of MgADP. Login to comment
140 In that study, diazoxide stimulated K1384M (NBF2 mutant) channels, but failed to stimulate K719A (NBF1 mutant) channels, leading to the suggestion that hydrolysis at NBF1 was most critical for diazoxide stimulation. Login to comment

PMID: 9755153 [PubMed] Schwanstecher M et al: "Potassium channel openers require ATP to bind to and act through sulfonylurea receptors."

No. Sentence Comment

112 For example, the substitution of an alanine for the conserved lysine in the Walker A motif in NBF1 (K719A) abolished diazoxide-induced activation of SUR1/ KIR6.2 channels, whereas substitution of a methionine at the equivalent position in NBF2 (K1384M) had a more subtle effect, eliminating activation by diazoxide in the presence of low (10 µM), but not high (100 µM) [ATP] (Gribble et al., 1997). Login to comment
115 On the other hand, substitution of a methionine in NBF2 of SUR1 (K1384M) does not reduce KCO binding at saturating ATP, but decreases the affinity for ATP (M.Schwanstecher et al., unpublished data). Login to comment

PMID: 10962016 [PubMed] Ribalet B et al: "Regulation of cloned ATP-sensitive K channels by phosphorylation, MgADP, and phosphatidylinositol bisphosphate (PIP(2)): a study of channel rundown and reactivation."

No. Sentence Comment

361 The hypothesis that phosphorylation of SUR1 favors binding of MgADP and thus functional coupling is supported by the observation that the K1384M mutation in SUR1`s second NBF completely suppress MgADP-dependent reactivation of ATP-inhibited channels (Gribble et al., 1997). Login to comment

PMID: 10099692 [PubMed] Seino S et al: "ATP-sensitive potassium channels: a model of heteromultimeric potassium channel/receptor assemblies."

No. Sentence Comment

204 However, mutations of lysine residues in the Walker A motifs in NBF-1 (K719A) and/or the equivalent mutation in NBF-2 (K1384M) of SUR1 do not prevent channel inhibition by ATP (36). Login to comment
207 In contrast, neither the NBF-1 mutant K719A channel nor the NBF-2 mutant K1384M channel is activated by MgADP (36). Login to comment
210 A mutation in the Walker A motif in NBF-1 (K719A) abolishes channel activation by diazoxide, but a mutation in the Walker A motif in NBF-2 (K1384M) does not affect the channel activation (36). Login to comment

PMID: 9238070 [PubMed] Trapp S et al: "Activation and inhibition of K-ATP currents by guanine nucleotides is mediated by different channel subunits."

No. Sentence Comment

14 We also showed that mutation of the lysine residue in the Walker A motif of either the first (K719A) or second (K1384M) nucleotide-binding domain of SUR1 abolished both the potentiatory effects of GTP and GDP on K-ATP currents and their ability to support stimulation by diazoxide. Login to comment
38 We examined the effects of mutating the WA lysine in either the first (K719A) or second (K1384M) NBD. Login to comment
95 We refer to these as K719A (wild-type Kir6.2 coexpressed with K719A-SUR1) and K1384M (wild-type Kir6.2 coexpressed with K1384M-SUR1). Login to comment
96 In contrast to wild-type K-ATP currents, neither K719A nor K1384M currents were activated by GTP (Fig. 2A). Login to comment
97 Instead, increasing GTP concentrations simply produced a dose-dependent inhibition of both K719A and K1384M currents (Fig. 2B). Login to comment
98 For K719A currents, the Ki for current inhibition was 2.7 Ϯ 0.6 mM and the Hill coefficient was 1.0 Ϯ 0.2 (n ϭ 5), and for K1384M currents, the Ki was 3.3 Ϯ 0.5 mM and the Hill coefficient was 1.4 Ϯ 0.2 (n ϭ 5). Login to comment
102 (A) Macroscopic currents recorded from three different inside-out patches in response to a series of voltage ramps from -110 to ϩ100 mV. Oocytes were coinjected with mRNAs encoding Kir6.2 and either wild-type SUR1, K719A-SUR1, or K1384M-SUR1 mRNAs. Login to comment
111 Neither K719A nor K1384M currents were activated by 100 ␮M GDP. Login to comment
115 The lack of an inhibitory effect of 1 mM GDP on K719A or K1384M currents suggests that at this concentration GDP exerts only a stimulatory effect on wild-type K-ATP currents. Login to comment
116 MgGDP (10 mM) blocked K719A and K1384M currents by 30 Ϯ 5% and by 55 Ϯ 6%, respectively (Fig. 3C). Login to comment
117 The extent of this inhibition suggests that GDP does not interact as strongly as ADP with the inhibitory binding site, since as little as 100 ␮M ADP blocked K719A and K1384M currents by Ͼ60% (13). Login to comment
121 We therefore examined the ability of guanine nucleotides to support the action of diazoxide on wild-type, K719A, and K1384M currents. Login to comment
131 (A) Macroscopic currents recorded from three different inside-out patches in response to a series of voltage ramps from -110 to ϩ100 mV. Oocytes were coinjected with mRNAs encoding Kir6.2 and either wild-type SUR1, K719A-SUR1, or K1384M-SUR1. Login to comment
138 Diazoxide was without effect on K1384M currents in the presence of guanine nucleotides. Login to comment
144 The efficacy of block was comparable to that observed for wild-type Kir6.2 when coexpressed with mutant SUR1: half-maximal inhibition was 6.0 mM for Kir6.2⌬C26 currents, 2.7 mM for K719A currents, and 3.3 mM for K1384M currents. Login to comment
148 This may explain why the K719A and K1384M currents appear slightly more sensitive to GTP than Kir6.2⌬C26 currents. Login to comment
155 (A) Macroscopic currents recorded from three different inside-out patches in response to a series of voltage ramps from -110 to ϩ100 mV. Oocytes were coinjected with mRNAs encoding Kir6.2 and either wild-type SUR1, K719A-SUR1, or K1384M-SUR1. Login to comment
167 One explanation for the inability of guanine nucleotides to enhance K719A or K1384M currents is that mutation of the WA lysines abolishes binding of either GTP or GDP. Login to comment
172 The fact that neither GTP nor GDP activate native K-ATP currents in the absence on Mg2ϩ (13), or K719A or K1384M currents in the presence of Mg2ϩ , is consistent with this hypothesis. Login to comment
174 We further show that mutation of the WA lysine at NBD1 (K719A) completely abolishes, while mutation of that at NBD2 (K1384M) very substantially reduces, the ability of GTP or GDP to support diazoxide activation. Login to comment

PMID: 9618560 [PubMed] Gribble FM et al: "MgATP activates the beta cell KATP channel by interaction with its SUR1 subunit."

No. Sentence Comment

7 Both of these effects were abolished when mutations were made in the NBDs of SUR1 that are predicted to abolish MgATP binding and/or hydrolysis (D853N, D1505N, K719A, or K1384M). Login to comment

PMID: 12031979 [PubMed] Dabrowski M et al: "The novel diazoxide analog 3-isopropylamino-7-methoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide is a selective Kir6.2/SUR1 channel opener."

No. Sentence Comment

154 Specifically, we mutated lysine 719 to alanine [SUR1(K719A)] and lysine 1384 to methionine [SUR1(K1384M)]. Login to comment
161 In this respect, NNC 55-9216 differs from diazoxide, which is still able to induce some activation of Kir6.2/SUR1(K1384M) currents (33). Login to comment
155 Specifically, we mutated lysine 719 to alanine [SUR1(K719A)] and lysine 1384 to methionine [SUR1(K1384M)]. Login to comment
162 In this respect, NNC 55-9216 differs from diazoxide, which is still able to induce some activation of Kir6.2/SUR1(K1384M) currents (33). Login to comment

PMID: 9350615 [PubMed] Gribble FM et al: "The interaction of nucleotides with the tolbutamide block of cloned ATP-sensitive K+ channel currents expressed in Xenopus oocytes: a reinterpretation."

No. Sentence Comment

13 When SUR1 was mutated to abolish MgADP activation of KATP currents (K719A or K1384M), there was no difference in the extent of tolbutamide inhibition in the presence or absence of MgADP. Login to comment
15 The Ki for tolbutamide interaction with either the high- or low-affinity site was unaffected by 100 /SM MgADP, for both wild-type and K719A-K1384M currents. Login to comment
17 MgGDP (100 /M) enhanced wild-type KATP currents and was without effect on K719A-K1384M currents. Login to comment
55 The lysine residues at position 719 or 1384 of SUR1 were replaced by an alanine or methionine, respectively (K719A, K1384M). Login to comment
107 Mutation of the WA lysine residues in either NBD1 (K719A) or NBD2 (K1384M), or both (K719A-K1384M) prevented the MgADP activation of KATP currents and unmasked the inhibitory effect of MgADP (Figs 2C and 4; Gribble et al. 1997 b). Login to comment
108 In the absence A 1 nA Tolbutamide B 30 s 0-5 nA MgADP Tolbutamide of nucleotides, the extent of block of K719A-K1384M, K719A and K1384M currents by 0 5 mm tolbutamide was similar to that of wild-type channels (Fig. 3). Login to comment
111 Effects of MgADP and tolbutamide on K719A-K1384M currents Macroscopic currents recorded from inside-out patches in response to a series of voltage ramps from -110 to +100 mV (holding potential, 0 mV). Login to comment
112 The oocytes were coinjected with mRNAs encoding wild-type Kir6.2 and K719A-K1384M SUR1. Login to comment
122 K719A-K1384M currents by 67 % (Fig. 2C). Login to comment
124 Furthermore, MgADP did not enhance tolbutamide inhibition of K719A-K1384M currents (Figs 2 and 3). Login to comment
125 Similar results were observed for K719A and K1384M currents (Figs 3 and 4), which confirms that the WA lysine at each of the NBDs of SUR1 is needed both for the stimulatory effect of MgADP itself 150 - 100 -1. Login to comment
141 O (dashed line), K719A-K1384M currents (n = 6). Login to comment
144 K719A-K1384M channel currents: K11 = 1'6 /M, h1 = 0-7, K42 = 2-1 mM, h2==14, L = 0'40. Login to comment
152 O, K719A-K1384M currents, 100 /uM MgADP (n = 6). Login to comment
154 In the presence of 100 ,UM MgADP: Kj1 = 6-6 ,UM, h1 = 1.1, K12= 43 mM, h2= 1-0, L = 0-13,A =4-3, B= 0-33, for wild-type channel currents; and Kj1= 3-1 um, h1= 12, K12=5-5mM, h2=1,L=044,A=1 0,B=033,for K719A-K1384M currents. Login to comment
158 A, K719A-K1384M currents, 100 /uM MgGDP (n = 6). Login to comment
160 In the presence of 100 /uM MgGDP: Kj1 = 60 FuM, h1 = 1 0, K12 = 2-0 mm, h2 = 1 0, L = 0.39, A = 1 9, B = 0 9, for wild-type channel currents; and Ki = 3-8 FuM, h,= 10, K2= 28 mM, h2= 1-3, L= 0-56, A = 1 0, B= 0-9, for K719A-K1384M currents. Login to comment
161 1000 100000.01 0.1 1 10 100 [Tolbutamide] (uM) 40 J. Physiol.504.1 We next examined the dose-response curve for tolbutamide block of K719A-K1384M currents. Login to comment
172 Unlike wild-type KATP currents, K719A-K1384M channel currents were blocked by 100 /LM MgADP (by 63-4 + 2-8%, n = 17). Login to comment
175 The best fit to the mutant channel currents in 100 /M MgADP was obtained with a K1 of 3-1 uM (2-1-4-7 /tM, n = 5), which is not significantly different (ANOVA) from that of wild-type currents, or K719A-K1384M currents in the absence of ADP. Login to comment
178 This would account for the fact that MgADP has no effect on the tolbutamide block of K719A-K1384M currents, which are not stimulated by the nucleotide. Login to comment
192 This confirms that MgGDP is able to act at the stimulatory nucleotide-binding site in wild-type, but not K719A-K1384M, channels. Login to comment
237 Second, the tolbutamide block of K719A-K1384M currents, which are not potentiated by MgADP, was not altered by MgADP. Login to comment
240 Since Mg2+ is required for the stimulatory effects of MgADP and MgGDP (Bokvist et al. 1991; Gribble et al. 1997 b), our results may also explain why nucleotide diphosphates only influence tolbutamide inhibition of KATP currents in the presence of Mg2+; in the absence of Mg2+, the effects of ADP would resemble those found for K719A-K1384M currents. Login to comment

PMID: 9135131 [PubMed] Gribble FM et al: "The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide."

No. Sentence Comment

10 In addition to its well- residues in the Walker A (WA) motifs of the first known inhibitory effect, Mg-ATP enhances channel (K719A) and second (K1384M) nucleotide-binding activity as evidenced by the fact that when Mg-ATP is domains (NBDs) of SUR1. Login to comment
19 When type and K1384M currents, but not K719A or K719A/ Mg2ϩ is present, however, high concentrations of ADP are K1384M currents, suggesting that there may be a inhibitory whereas low concentrations potentiate channel factor in addition to ATP and ADP which regulates activity (Dunne and Petersen, 1986; Kakei et al., 1986; K-ATP channel activity. Login to comment
45 We also found that metabolic inhibition led to activation ofγ and β phosphate groups of ATP and is essential for ATP hydrolysis (Azzaria et al., 1989; Saraste et al., 1990; Tian wild-type and K1384M currents, but not K719A or K719A/ K1384M currents. Login to comment
56 This may be attributed to relief of the blockingcritical lysine in the WA motifs of either NBD1 (K719A) or NBD2 (K1384M), or both (K719A/K1384M), of SUR1, effect of cytoplasmic ATP (Gribble et al., 1997). Login to comment
59 The mean current amplitudes at -100 mV following patch excision were: -3.9 Ϯ 0.8 nAseverely impair nucleotide hydrolysis without significantly affecting nucleotide binding (Azzaria et al., 1989; Saraste (n ϭ 12) for wild-type, -2.2 Ϯ 0.8 nA (n ϭ 12) for K719A, -5.0 Ϯ 1.9 nA (n ϭ 11) for K1384M and -2.6 Ϯ 0.9 nA (n ϭet al., 1990; Tian et al., 1990; Higgins, 1992; Carson et al., 1995; Ko and Pedersen, 1995). Login to comment
60 Our results indicate 8) for K719A/K1384M. Login to comment
68 Mutant (n ϭ 8) for K719A, 15.7 Ϯ 0.2 µM (n ϭ 6) for K1384M and 16.5 Ϯ 0.3 µM (n ϭ 5) for K719A/K1384M. Login to comment
79 Oocytes were coinjected with mutant channels showed 'refreshment` in the presence ofmRNAs encoding Kir6.2 and either wild-type SUR1, K719A-SUR1, Mg2ϩ (Figure 2A), it is unlikely that the ATP hydrolysisK1384M-SUR1 or the double SUR1 mutant K719A/K1384M. Login to comment
81 channels (d, n ϭ 10) and the mutant K-ATP channels K719A (j, n ϭ 8), K1384M (u, n ϭ 6) or K719A/K1384M (s, n ϭ 5). Login to comment
92 The Hill coefficients were unaffected by mutation of the WA lysines, being Furthermore, both NBDs are required for channel activation: interaction of Mg-ADP with a single NBD is not1.03 Ϯ 0.06 (n ϭ 10) for currents formed from Kir6.2 and wild-type SUR1, 0.99 Ϯ 0.10 (n ϭ 8) for K719A, sufficient because neither K719A nor K1384M currents were enhanced by Mg-ADP. Login to comment
93 In this context, it is of interest1.35 Ϯ 0.13 (n ϭ 6) for K1384M and 0.99 Ϯ 0.14 (n ϭ 5) for K719A/K1384M (n.s., ANOVA). Login to comment
109 Figure 6A shows that, K719A-SUR1, K1384M-SUR1 or the double SUR1 mutant K719A/ in the presence of 100 µM Mg-ATP, diazoxide activatedK1384M; 100 µM MgATP and 100 µM MgADP were added to the both wild-type and K1384M currents but did not affectinternal solutions as indicated by the bars. Login to comment
110 K719A or K719A/K1384M currents. Login to comment
111 When Mg-ATP was reduced to 10 µM, wild-type currents were enhanced by diazoxide, K719A and K719A/K1384M were inhibited(Figure 5). Login to comment
112 The extent of this inhibition was comparable with that observed for wild-type channels when ADP was and K1384M was unaffected (Figure 6B). Login to comment
115 Diazoxide acted more slowly on K1384M than the wild-type channelwere also similar for wild-type and mutant channels. Login to comment
118 The reduced ATP sensitivity of the wild-type channel (Figure 2B) may thus The effects of diazoxide in the presence of the nucleotide diphosphate Mg-ADP are summarized in Figure 6C. Inresult from a simultaneous activation by Mg-ADP (formed from hydrolysis of Mg-ATP) which does not occur in WA the presence of 100 µM Mg-ADP, diazoxide slightly potentiated wild-type and K1384M currents and inhibitedmutant channels. Login to comment
119 The fact that the percentage block of the WA mutant currents by Mg-ADP is smaller in the presence K719A and K719A/K1384M currents. Login to comment
130 A third(measured between -20 and -100 mV) by 15.3 Ϯ 1.6% (n ϭ 8) in wild-type channels, by 17.4 Ϯ 0.6% (n ϭ 5) possibility, which cannot be completely excluded, is that our ADP solution contains a small quantity of ATP eitherin K719A channels, 18.2 Ϯ 1.0% (n ϭ 4) in K1384M channels and by 12.9 Ϯ 2.3% (n ϭ 6) in K719A/K1384M as a contaminant or formed from ADP by the action by enzymes present in the patch membrane.channels (n.s., ANOVA). Login to comment
136 The number of oocytes was: wild type (n ϭ 13), K719A (n ϭ 8), K1384M (n ϭ 12) and K719A/K1384M (n ϭ 5). Login to comment
162 Metabolic inhibition increased, and diazoxide further potentiated both wild-type and K1384M whole- ATP sensitivity reported for native K-ATP channels in the absence of Mg2ϩ (Ashcroft and Kakei, 1989).cell currents but was without effect in oocytes expressing K719A or K719A/K1384M. Login to comment
182 We Carson et al., 1995; Ko and Pedersen, 1995; Koronakis speculate that nucleotide binding, or hydrolysis, at NBD1 et al., 1995), a similar effect may be expected for K719A, potentiates or prolongs K-ATP channel opening and that K1384M and K719A/K1384M. Login to comment
188 A second possibility, therefore, is that to channel activation in intact oocytes, because whole- MgADP hydrolysis at the NBDs might produce some cell K1384M currents, but not K719A currents, were conformational change in SUR1 which enhances K-ATP activated by exposure to azide. Login to comment
190 If this idea is correct, then hydrolysis at K1384M channels have similar ATP sensitivities and both NBDs must be required to sustain channel activation neither are upregulated by 100 µM Mg-ADP, this result because mutation of only one NBD removed the ability also argues that, in addition to ATP and ADP, there may of Mg-ADP to activate the current. Login to comment