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J Biol Chem, Vol. 274, Issue 40, 28079-28082, October 1, 1999

COMMUNICATION
Identification of the Potassium Channel Opener Site on Sulfonylurea Receptors^*

Ingo Uhde, Andreas Toman, Insa Gross, Christina Schwanstecher, and Mathias Schwanstecher^§

From the Institut für Pharmakologie und Toxikologie, Universität Braunschweig, Mendelssohnstraße 1, 38106 Braunschweig, Germany

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Diversity of sulfonylurea receptor (SUR) subunits underlies tissue specific pharmacology of K_ATP channels, which represent critical regulators of electrical activity in numerous cells. Notably, the neuronal/pancreatic -cell receptor, SUR1, imparts high sensitivity to hypoglycemic sulfonylureas (SUs; e.g. glibenclamide) and low to potassium channel openers (KCOs; e.g. P1075), whereas the opposite drug sensitivities are conferred by cardiovascular receptors, SUR2A and SUR2B. By exchanging domains between SUR1 and SUR2B, we identify two regions (KCO I: Thr¹⁰⁵⁹-Leu¹⁰⁸⁷ and KCO II: Arg¹²¹⁸-Asn¹³²⁰; rat SUR2 numbering) within the second set of transmembrane domains (TMDII) as critical for KCO binding. Swapping both regions reconstitutes KCO affinities and sensitivities of the donor SUR isoform. High glibenclamide affinity of SUR1 is not reduced by transfer of KCO I plus II from SUR2B, demonstrating that high SU and KCO affinity can coexist in the same SUR molecule. Consistently, high SU affinity was imparted on SUR2B by substituting the region separating KCO I and II (Ile¹⁰⁸⁸-Val¹²¹⁷) with the corresponding domain of SUR1. We infer the receptor sites for KCOs and SUs to be closely associated within a regulatory domain (Thr¹⁰⁵⁹-Asn¹³²⁰) in TMDII of SURs.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Potassium channel openers (KCOs)¹ comprise a structurally diverse group of drugs with a broad spectrum of potential therapeutic applications (e.g. hypoglycemia, hypertension, arrhythmias, angina pectoris, asthma) (1). These drugs (e.g. P1075, pinacidil, levcromakalim, diazoxide) exert their effects on secretory cells, neurones, vascular and nonvascular smooth muscle, and on cardiac and skeletal muscle by opening ATP-sensitive potassium channels (K_ATP channels), thus shifting the membrane potential toward the reversal potential for potassium and reducing cellular electrical activity (2).

Recent progress resulted in cloning of K_ATP channels and elucidation of their subunit composition (see Ref. 3 for a review). These channels are assembled with a tetradimeric stoichiometry, (SUR/Kir6.x)₄, from two structurally distinct subunits, an inwardly rectifying potassium channel subunit (K_IR6.1 or K_IR6.2) forming the pore and a regulatory subunit, a sulfonylurea receptor (SUR), belonging to the ATP-binding cassette superfamily with multiple transmembrane domains (TMDs) and two nucleotide binding folds (NBFs) (4-11).

Three isoforms of SURs have been cloned, SUR1 and two splice products of a single gene, SUR2A and SUR2B, differing only in their C-terminal 42-45 amino acids (4, 6, 8, 12). SUR1/K_IR6.2 have been proposed to reconstitute the neuronal/pancreatic -cell (5), SUR2A/K_IR6.2, the cardiac (6, 13, 14), and SUR2B/K_IR6.1 (or K_IR6.2), the vascular smooth muscle-type K_ATP channels (8, 11, 15, 16).

Notably, diversity of SURs confers tissue-specific pharmacology, with SUR2 isoforms imparting high sensitivity to KCOs and low to sulfonylureas (SUs) and SUR1 mediating inverse sensitivities (5, 6, 8, 16-18). Unraveling the molecular basis for these divergent drug sensitivities and understanding the mechanisms involved in drug-induced modulation of K_ATP channel activity is of key importance for design of tissue specific compounds.

Here, we report two regions within the second set of transmembrane domains (TMDII) of SURs to be essential for KCO binding and action.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Materials and Solutions-- [³H]P1075 (specific activity 116 Ci mmol¹) was purchased from Amersham Pharmacia Biotech Freiburg, Germany). [³H]Glibenclamide (specific activity 51 Ci mmol¹) was from NEN Life Science Products (Dreieich, Germany). All other chemicals and drugs were obtained from the sources described elsewhere (16, 18-20). Stock solutions of drugs were prepared in KOH (50 mM) or dimethyl sulfoxide with a final solvent concentration in the media below 1%.

Molecular Biology-- Chimeras comprising segments from hamster SUR1 (GenBank^TM accession number A56248) or rat SUR2B (GenBank^TM accession number AF087838) were constructed using standard molecular biology techniques. Products were subcloned into the pECE vector (4) and sequenced to verify constructs and polymerase chain reaction fidelity before transfection.

Composition of chimeras was as follows (numbers indicate amino acid boundaries of SUR2B or SUR1 as indicated; see also Fig. 1A): chimera I (1-675, SUR2B)-(687-901, SUR1)-(880-1545, SUR2B); chimera II (1-1087, SUR2B)-(1121-1250, SUR1)-(1218-1545, SUR2B); chimera III (1-1320, SUR2B)- (1358-1582, SUR1); chimera IV (1-919, SUR2B)-(942-1091, SUR1)-(1059-1545, SUR2B); chimera V (1-686, SUR1)-(676-1545, SUR2B); chimera VI (1-1058, SUR2B)-(1092-1120, SUR1)-(1088-1545, SUR2B); chimera VII (1-1217, SUR2B)-(1251-1357, SUR1)-(1321-1545, SUR2B); chimera VIII (1-1091, SUR1)-(1059-1087, SUR2B)-(1121-1582, SUR1); chimera IX (1-1250, SUR1)-(1218-1320, SUR2B)-(1358-1582, SUR1); chimera X (1-1091, SUR1)-(1059-1087, SUR2B)-(1121-1250, SUR1)-(1218-1320, SUR2B)-(1358-1582, SUR1).

Binding Experiments-- Transfections and membrane preparations were performed as described previously (16, 19). Briefly, COS-7 cells cultured in DMEM-HG (10 mM glucose), supplemented with 10% fetal calf serum, were plated at a density of 5 × 10⁵ cells per dish (94 mm) and allowed to attach overnight. 200 µg of pECE-SUR complementary DNA were used to transfect 10 plates. For transfection the cells were incubated 4 h in a Tris-buffered salt solution containing DNA (5-10 µg/ml) plus DEAE-dextran (1 mg/ml), 2 min in HEPES-buffered salt solution plus dimethyl sulfoxide (10%) and 4 h in DMEM-HG plus chloroquine (100 µM). Cells were then returned to DMEM-HG plus 10% fetal calf serum. Membranes were prepared 60-72 h posttransfection as described (19). For binding experiments resuspended membranes (final protein concentration 5-50 µg/ml) were incubated in Tris buffer (50 mM, pH 7.4) containing either [³H]P1075 (final concentration 3 nM, nonspecific binding defined by 100 µM pinacidil) or [³H]glibenclamide (final concentration 0.3 nM, nonspecific binding defined by 100 nM glibenclamide) and other additions as shown in the figure. The free Mg²⁺ concentration was kept close to 0.7 mM. In P1075 assays (Fig. 1, A and B), MgATP (0.1 mM) was added to incubation media to enable KCO binding (16). Low affinity P1075 binding to SUR1 isoforms (Fig. 1A) was measured via allosteric displacement of [³H]glibenclamide as described previously (16). Incubations were carried out for 1 h at room temperature and were terminated by rapid filtration through Whatman GF/B filters.

Electrophysiology-- Transfections were performed as described above with the following modification. COS-7 cells were plated at a density of 8 × 10⁴ cells per dish (35 mm). 20 µg of pECE-SUR complementary DNA and 20 µg of pECE-mouse K_IR6.2 complementary DNA (GenBank^TM D50581) were mixed and used to transfect six 35-mm plates. Experiments in the inside-out configuration of the patch-clamp technique were performed 1-2 days after transfection at room temperature as described previously (20). Membrane patches were clamped at 50 mV. The intracellular bath solution contained (mM) 140 KCl, 2 CaCl₂, 0.7 free Mg²⁺, 10 EGTA, 5 HEPES (pH 7.3) and the pipette solution 146 KCl, 2.6 CaCl₂, 1.2 MgCl₂, and 10 HEPES (pH 7.4). For registration of concentration-response curves (Fig. 1D) patches were chosen with little "run-down" over the measuring period and drug effects were corrected for this loss of channel activity by use of linear interpolation. Artifacts due to incomplete drug washout or slow reversibility were excluded by making sure that cumulative experiments with stepwise increase or decrease of the drug concentration yielded identical EC₅₀ values and slope factors. Channel activity (A) was defined as the product of the number of functional channels (n) and the probability of the channels being in the open state (p). A was calculated by dividing the mean current (I) by the single-channel current amplitude (i). Density of K_ATP channels per patch ranged from 15 to 50. Varying channel densities did not affect EC₅₀ values or Hill coefficients.

Data-- Data analysis (including calculation of K_D values from IC₅₀ values), and statistics were performed as described (19, 20). Results shown as mean ± S.E. (n = 3-16).

	RESULTS

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

The pharmacological hallmark of SUR2B is its high affinity for KCOs, the K_D for P1075 (rat; 11 ± 2 nM) being approximately 100,000-fold lower than that of SUR1 (hamster; 1.06 ± 0.1 mM; see also Ref. 16). Based on this huge affinity difference the KCO receptor site was localized by systematically substituting corresponding domains between both isoforms (Fig. 1A).

View larger version (50K): [in this window] [in a new window]   Fig. 1.   Localization of the KCO receptor site on SURs. A, two regions within TMDII are essential for high affinity KCO binding. Schemata of chimeric constructs are shown on the left (for details see "Experimental Procedures"), and dissociation constants (KD values) for binding of P1075 are shown on the right of the figure. Displacement of [3H]P1075 (3 nM (a)) or [3H]glibenclamide (0.3 nM (b)) by unlabeled P1075 was assessed using membranes from COS-7 cells transiently expressing wild type isoforms or chimeras. KD values are shown as mean ± S.E. calculated from half-maximally inhibitory concentrations (IC50 values) of n = 4-16 independent displacement curves (see part B). c, p < 0.05 for the comparison with SUR2B. d, p < 0.05 for the comparison with SUR1. n.d., not detectable (affinity was too low for detection of specific [3H]P1075 or [3H]glibenclamide binding). KD values were: 11 ± 2 nM (SUR2B), 1.06 ± 0.1 mM (SUR1), 13 ± 2 nM (I), 14 ± 2 nM (II), 10 ± 1 nM (III), 31 ± 5 nM (IV), 48 ± 4 nM (V), 0.65 ± 0.08 mM (VIII), 0.24 ± 0.04 mM (IX), 0.17 ± 0.02 µM (X). B, binding affinities of KCOs for chimera X. [3H]P1075 (3 nM) displacement assays (n = 4-5) were done with membranes from COS-7 cells expressing chimera X. IC50 values and Hill coefficients are: 0.17 ± 0.02 µM, 0.91 (P1075, ); 1.8 ± 0.2 µM, 0.98 (pinacidil, ); 10 ± 2 µM, 1.09 (levcromakalim, ). Curves for SUR2B taken from Ref. 16. C, P1075-induced activation of channels reconstituted in COS-7 cells by expression of SUR subunits with KIR6.2 as indicated. Representative currents recorded from inside-out patches at 50 mV. Inward currents are shown as downward deflections. The patch was exposed to P1075 and ATP as indicated by the lines above the records. D, potencies of KCOs to open channels reconstituted with chimeras VII, X, or SUR1. Channel activation was recorded in inside-out patches as shown in part C. Results (n = 3-5) are expressed as percentage of maximal drug-induced channel activation (activity induced by 0.3 mM diazoxide, see Refs. 5 and 16). EC50 values (half-maximally effective concentrations) and Hill coefficients are: 0.61 ± 0.12 µM, 1.41 (P1075, ); 13 ± 5 µM, 1.28 (pinacidil, ); 52 ± 11 µM, 1.35 (levcromakalim, ). Curves for SUR2B taken from Ref. 16. E, SU affinities of chimeras II and X. Displacement of [3H]glibenclamide (0.3 nM) by unlabeled compounds (Glib = glibenclamide; Glip = glipizide; Tolb = tolbutamide; n = 4-5) was done with membranes from COS-7 cells expressing chimeras as indicated. IC50 values and Hill coefficients are: 1.5 ± 0.2 nM, 1.02 (II, Glib, ); 27 ± 4 nM, 0.94 (II, Glip, ); 24 ± 3 µM, 1.09 (II, Tolb, ); 0.98 ± 0.07 nM, 1.01 (X, Glib, ). Curves for SUR1 taken from Ref. 18. F, putative transmembrane topologies of the regions essential for KCO (KCO I and II) and SU (SUBR) binding. Potential topology was assigned by hydropathy analysis (26) assuming 17 TMDs (27). Filled circles represent amino acids within KCO I and II (sequence numbers indicate first or last amino acid; rat SUR2B numbering). G, amino acid sequence alignment of KCO I and II in SUR2B and SUR1 (divergent amino acids shown). ic = intracellular; tm = transmembrane; ec = extracellular.

Whereas both NBFs (chimera I and III; K_D = 13 ± 2 nM or 10 ± 1 nM, respectively) and TMDs 14-15 (chimera II; K_D = 14 ± 2 nM) did not contribute to discrepant affinities, small, 3-5-fold reductions of SUR2B's P1075 affinity were induced by replacing TMDs 12-13 (chimera IV; K_D = 31 ± 5 nM) or 1-11 (chimera V; K_D = 48 ± 4 nM), indicating these latter domains to interfere with the binding process either directly or indirectly. Two regions, part of the cytosolic loop between TMD 13 and 14 (KCO I: Thr¹⁰⁵⁹-Leu¹⁰⁸⁷; chimera VI) and TMDs 16-17 (KCO II: Arg¹²¹⁸-Asn¹³²⁰; chimera VII), however, were identified to be essential, with complete loss of detectable [³H]P1075 binding resulting from substitution. Consistently, combined transfer of these domains into SUR1 induced a 6,200-fold increase of P1075 affinity (chimera X; K_D = 0.17 ± 0.02 µM), whereas split substitutions mediated small, 1.5-4-fold enhancements (chimera VIII and IX; K_D = 0.65 ± 0.08 mM or 0.24 ± 0.04 mM, respectively), implying both domains to interact in formation of the KCO binding site.

Strong gain of P1075 affinity in chimera X was paralleled by affinity increments for pinacidil (270 fold; K_D = 1.8 ± 0.2 µM) and levcromakalim (>50-fold; K_D = 10 ± 2 µM), thus reconstituting the SUR2B characteristic rank order (Fig. 1B; see Ref. 16 for KCO binding to SUR1). Binding was matched by drug action (Fig. 1, C and D), with P1075 sensitivity of channels reconstituted with the loss-of-affinity constructs (chimera VI or VII) resembling that mediated by SUR1 (EC₅₀ > 1 mM; results shown for chimera VII only) and the gain-of-affinity chimera X conferring potencies (P1075, EC₅₀ = 0.61 ± 0.12 µM; pinacidil, EC₅₀ = 13 ± 5 µM; levcromakalim, EC₅₀ = 52 ± 11 µM) similar to wild type SUR2B.

Notably, glibenclamide affinity of chimera X (K_D = 0.68 ± 0.05 nM; Fig. 1E) equaled that of SUR1 (K_D = 0.72 nM; Ref. 18), suggesting KCO I and II not to form part of the SU receptor site and indicating that high affinity binding of SUs and KCOs can be combined within the same isoform.

A region overlapping that separating KCO I and II was recently reported to be critical for SU sensitivity (21). Consistently, we found substitution of this linking region (SUBR: Ile¹⁰⁸⁸-Val¹²¹⁷; Fig. 1F) by the corresponding domain of SUR1 (Ile¹¹²¹-Val¹²⁵⁰; chimera II) to significantly enhance SU affinities (210-fold for glibenclamide, K_D = 1.2 ± 0.15 nM; 280-fold for glipizide, K_D = 22 ± 3 nM; 14-fold for tolbutamide, K_D = 19 ± 2 µM; see Ref. 18 for SU binding to SUR 2B) with dissociation constants resembling that of wild type SUR1 (Fig. 1E). Similar to KCOs, affinity increments were paralleled by drug action. Glibenclamide sensitivity of channels transiently reconstituted from chimera II plus K_IR6.2 (EC₅₀ = 0.22 ± 0.09 nM; n = 4; results not shown in a figure) was 190-fold higher than that of SUR2B/K_IR6.2 channels (EC₅₀ = 42 nM; Ref. 18) coinciding with the drug's potency to inhibit activity of SUR1/K_IR6.2 channels (EC₅₀ = 0.13 nM; Ref. 18).

Expression rates of the chimeras did not differ markedly from that of the wild type receptors, ranging from 10 to 50 pmol/mg of membrane protein as calculated from maximal number of binding sites (chimeras I-V and VIII-X) or estimated from reconstituted channel activity (chimeras VI and VII).

	DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

This study is the first to localize regions in SURs critical for formation of the KCO binding pocket and to establish that high affinity KCO and SU binding can coexist within the same isoform. These conclusions are based on the following findings. 1) Substitution of two regions within TMDII of SUR2B (KCO I and II, Fig. 1F) with the corresponding domains of SUR1 (chimera VI and VII) induced a complete loss of detectable [³H]P1075 binding (Fig. 1A). 2) Simultaneous transfer of these regions into SUR1 (chimera X) strongly increased KCO affinities (6,200-fold for P1075) reproducing the SUR2B characteristic binding pattern for P1075, pinacidil, and levcromakalim (Fig. 1, A and B). 3) High glibenclamide affinity of SUR1 was not reduced by this transfer (Fig. 1E). 4) Loss or gain of KCO affinity were paralleled by corresponding sensitivity changes of channels reconstituted with K_IR6.2 (Fig. 1, C and D).

The regions critical for KCO binding reside in TMDII forming part of the putative intracellular loop connecting TMD 13 and 14 (KCO I: Thr¹⁰⁵⁹-Leu¹⁰⁸⁷, SUR2 numbering) and the domain preceding NBF2 (KCO II: Arg¹²¹⁸-Asn¹³²⁰, SUR2 numbering) (Fig. 1F). Either of the two regions proved essential for reconstitution of the SUR2B characteristic pattern of high KCO affinities, strongly arguing that both domains interact in formation of the binding pocket. However, since TMDs 1-11 (chimera V) and 12-13 (chimera IV) were required for full KCO affinity, additional regions might be involved (Fig. 1A). Similarly, we have shown recently that the C-terminal 42 amino acids affect KCO affinity by a factor of 3-5 with SUR1 = SUR2B > SUR2A (16).

Identification of KCO I in a putative intracellular loop suggests localization of the receptor site at the internal face of the plasma membrane implying that, equivalent to SUs (20), KCOs have to cross the membrane to exert their effect. This finding also hints the putative intracellular part of KCO II (Ala¹²⁶⁶-Asn¹³²⁰, SUR2B numbering; Fig. 1, F and G) to act as counterpart of KCO I in formation of the site. Albeit, limiting substitutions to this part of KCO II (plus KCO I) did not lead to reconstitution of high KCO affinity (results not shown).

Importantly, high SU affinity could be conferred on SUR2B by substituting the region separating KCO I and II (SUBR: Ile¹⁰⁸⁸-Val¹²¹⁷, SUR2 numbering; Fig. 1F) by the corresponding domain of SUR1 (chimera II). Since this transfer did perfectly reconstitute affinities of SUR1 for glibenclamide, glipizide, and tolbutamide (Fig. 1E), the results strongly suggest SUBR to form the SU binding site, thus supporting conclusions from a recent study (21).

We infer TMDs 14-17 (Thr¹⁰⁵⁹-Asn¹³²⁰, SUR2 numbering) within TMDII of SURs to be of key importance for drug-induced K_ATP channel modulation with the core region of this regulatory domain forming the binding site for SUs (SUBR) and the flanking regions (KCO I and KCO II) constituting main parts of the receptor site for KCOs (Fig. 1F). The idea of distinct (although closely associated) sites is supported by substitution of SUBR lacking an effect on P1075 affinity (chimera II, Fig. 1A) and transfer of KCO I and II not affecting the K_D for glibenclamide (chimera X, Fig. 1, A and E). Close local association of SU and KCO binding regions, on the other hand, conforms with evidence for negative allosteric coupling of the sites (15, 16, 18, 19, 22-24).

Notably, pharmacological properties of SUR1 and SUR2B were combined in either chimera II and X (Fig. 1, A and E), thus establishing for the first time high affinity for KCOs and SUs not to be mutually exclusive. Hence, native SUR isoforms with similar properties might exist, and accordingly evidence for a receptor with high P1075 and glibenclamide affinity has been presented recently in vascular smooth muscle (25). Both chimeras provide excellent tools for further analysis of functional interaction between the drug sites.

High KCO and SU affinities of chimeras II and X matched sensitivities of channels transiently reconstituted with K_IR6.2 (see "Results" and Fig. 1, B-E). This finding implies that SUR isoforms use identical mechanisms to transduce drug binding to the regulatory domain (KCO I + SUBR + KCO II; Thr¹⁰⁵⁹-Asn¹³²⁰, SUR2 numbering; Fig. 1F) into modulation of channel activity.

It might be argued that the regulatory domain does not form the receptor sites itself but indirectly affects KCO or SU binding in other regions. Although this possibility cannot be ruled out, it is unlikely to explain restitution of the correct rank order of affinities (Fig. 1, B and E).

The study provides new insight into the molecular mechanisms of drug-induced K_ATP channel regulation. We conclude the receptor sites for KCOs and SUs to be closely associated within a regulatory domain in TMDII of SURs.

	ACKNOWLEDGEMENTS

We are grateful to Dr. Lydia Aguilar-Bryan and Dr. Joseph Bryan (Baylor College of Medicine, Houston, TX) for the hamster SUR1 clone and stimulating discussions. We thank Haide Fürstenberg, Ursula Herbort-Brand, Gisela Müller, Claudia Ott, Beate Pieper, and Carolin Rattunde for excellent technical assistance.

	FOOTNOTES

^* This work was supported by grants from the Deutsche Forschungsgemeinschaft (to M. S. and C. S.).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.

These authors contributed equally to this work.

^§ To whom correspondence should be addressed. E-mail: m.schwanstecher@tu-bs.de.

	ABBREVIATIONS

The abbreviations used are: KCO, potassium channel opener; K_ATP, ATP-sensitive K⁺ channel; KCO I and KCO II, potassium channel opener binding regions; K_IR, inwardly rectifying K⁺ channel; NBF, nucleotide binding fold; SU, sulfonylurea; SUBR, sulfonylurea binding region; SUR, sulfonylurea receptor; TMD, transmembrane domain; TMDI or TMDII, first (1-11) or second (12-17) set of transmembrane domains (see Fig. 1, A or F); DMEM, Dulbecco's modified Eagle's medium.

	REFERENCES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

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				A. P. Babenko and J. Bryan SUR-dependent Modulation of KATP Channels by an N-terminal KIR6.2 Peptide. DEFINING INTERSUBUNIT GATING INTERACTIONS J. Biol. Chem., November 8, 2002; 277(46): 43997 - 44004. [Abstract] [Full Text] [PDF]

				A. Hambrock, R. Preisig-Muller, U. Russ, A. Piehl, P. J. Hanley, J. Ray, J. Daut, U. Quast, and C. Derst Four novel splice variants of sulfonylurea receptor 1 Am J Physiol Cell Physiol, August 1, 2002; 283(2): C587 - C598. [Abstract] [Full Text] [PDF]

				M. Dabrowski, F. M. Ashcroft, R. Ashfield, P. Lebrun, B. Pirotte, J. Egebjerg, J. Bondo Hansen, and P. Wahl The Novel Diazoxide Analog 3-Isopropylamino-7-Methoxy-4H-1,2,4-Benzothiadiazine 1,1-Dioxide Is a Selective Kir6.2/SUR1 Channel Opener Diabetes, June 1, 2002; 51(6): 1896 - 1906. [Abstract] [Full Text] [PDF]

				C. Loffler-Walz, A. Hambrock, and U. Quast Interaction of KATP Channel Modulators with Sulfonylurea Receptor SUR2B: Implication for Tetramer Formation and Allosteric Coupling of Subunits Mol. Pharmacol., February 1, 2002; 61(2): 407 - 414. [Abstract] [Full Text] [PDF]

				U. Russ, U. Lange, C. Loffler-Walz, A. Hambrock, and U. Quast Interaction of the Sulfonylthiourea HMR 1833 with Sulfonylurea Receptors and Recombinant ATP-Sensitive K+ Channels: Comparison with Glibenclamide J. Pharmacol. Exp. Ther., December 1, 2001; 299(3): 1049 - 1055. [Abstract] [Full Text] [PDF]

				F. Reimann, F. M. Ashcroft, and F. M. Gribble Structural Basis for the Interference Between Nicorandil and Sulfonylurea Action Diabetes, October 1, 2001; 50(10): 2253 - 2259. [Abstract] [Full Text]

				A. Hambrock, C. Loffler-Walz, U. Russ, U. Lange, and U. Quast Characterization of a Mutant Sulfonylurea Receptor SUR2B with High Affinity for Sulfonylureas and Openers: Differences in the Coupling to Kir6.x Subtypes Mol. Pharmacol., July 1, 2001; 60(1): 190 - 199. [Abstract] [Full Text]

				T. Krauter, J. P. Ruppersberg, and T. Baukrowitz Phospholipids as Modulators of KATP Channels: Distinct Mechanisms for Control of Sensitivity to Sulphonylureas, K+ Channel Openers, and ATP Mol. Pharmacol., April 16, 2001; 59(5): 1086 - 1093. [Abstract] [Full Text]

				F. Reimann, F. M. Gribble, and F. M. Ashcroft Differential Response of KATP Channels Containing SUR2A or SUR2B Subunits to Nucleotides and Pinacidil Mol. Pharmacol., April 13, 2001; 58(6): 1318 - 1325. [Abstract] [Full Text]

				B. O'Rourke Myocardial KATP Channels in Preconditioning Circ. Res., November 10, 2000; 87(10): 845 - 855. [Abstract] [Full Text] [PDF]

				T. Matsuoka, K. Matsushita, Y. Katayama, A. Fujita, K. Inageda, M. Tanemoto, A. Inanobe, S. Yamashita, Y. Matsuzawa, and Y. Kurachi C-Terminal Tails of Sulfonylurea Receptors Control ADP-Induced Activation and Diazoxide Modulation of ATP-Sensitive K+ Channels Circ. Res., November 10, 2000; 87(10): 873 - 880. [Abstract] [Full Text] [PDF]

				M. BIENENGRAEBER, A. E. ALEKSEEV, M. R. ABRAHAM, A. J. CARRASCO, C. MOREAU, M. VIVAUDOU, P. P. DZEJA, and A. TERZIC ATPase activity of the sulfonylurea receptor: a catalytic function for the KATP channel complex FASEB J, October 1, 2000; 14(13): 1943 - 1952. [Abstract] [Full Text]

				R. M Shepherd, K. E Cosgrove, R. E O'Brien, P. D Barnes, C. Ämmälä, and M. J Dunne Hyperinsulinism of infancy: towards an understanding of unregulated insulin release Arch. Dis. Child. Fetal Neonatal Ed., March 1, 2000; 82(2): 87F - 97. [Abstract] [Full Text]