Future
Editorial Special Focus Issue: Rare Diseases
Medicinal Chemistry
For reprint orders, please contact [email protected]
Druggability of the inward rectifier family: a hope for rare channelopathies? “
With the recent identification of disease mutations in Kir4.1 (SeSAME/EAST syndrome) and Kir7.1 (snowflake vitreoretinal degeneration), it is clearly possible that additional Kir channelopathies will be identified in the future.
”
Keywords: arrhythmia • gating • heart • helix-bundle crossing • hypertension • hypotension • kidney • nephron • trafficking • rare diseases
The inward rectifier potassium (K ir) channel family is made up of 16 genes (KCNJx) encoding seven sub-families (K ir1–K ir7) of structurally related protein subunits. K ir channels are tetramers of identical (homomeric) or different (heteromeric) subunits, each possessing two transmembrane domains (M1 and M2), a pore loop, and a large cytoplasmic domain. The term ‘inward rectification’ refers to their preference for passing K+ current in the inward direction due to pore block of outward current by intracellular polyamines. K ir channels are pivotal regulators of electrical excitability in neurons and cardiomyocytes and mediate K+ transport in epithelial cells of the kidney tubule. Their importance in humans is underscored by the existence of rare, monogenic diseases caused by mutations in K ir channel-encoding genes [1] . With the emergence of enabling techno logies for K ir channel-directed drug discovery in pharmaceutical and academic laboratories, an important and timely question is whether K ir channels represent viable drug targets for these rare ‘channelopathies’. Bartter’s syndrome & Kir1.1 The life-threatening kidney disease, antenatal (type II) Bartter’s syndrome, is an autosomal recessive disorder caused by loss-of-function mutations in KCNJ1 [2] , which encodes the founding K ir1 channel family member K ir1.1 (also called the renal outer medullary K+ channel). Bartter’s syndrome presents early in life with polyhydramnios, preterm birth, failure to thrive, and chronic kidney dysfunction
10.4155/FMC.14.12 © 2014 Future Science Ltd
characterized by polyuria, low blood pressure, hypokalemia and metabolic alkalosis. Excessive urination results from a loss of NaCl reabsorption in the thick ascending limb of Henle’s loop and osmotically coupled water reabsorption in the distal nephron, both of which are dependent on K ir1.1 function in the thick ascending limb. Current treatments include cyclooxygenase inhibitors and potassium-sparing diuretics to limit urinary sodium and potassium loss, respectively. With a prevalence of 1 in 1,000,000 and more than 30 distinct mutations identified thus far, antenatal Bartter’s syndrome is both rare and genetically heterogeneous [2] . In general, Bartter’s mutations inhibit K ir1.1 function by:
Jerod S Denton Department of Anesthesiology, Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232, USA jerod.s.denton@vanderbilt. edu
• Impairing the biogenesis and trafficking of the channel to the cell surface; • Disrupting conformational ‘gating’ chan ges that enable channel opening; • A combination of both [3,4] . At least in heterologous expression systems, some trafficking mutants can be forced to the cell surface and functionally rescued by overexpression, presumably by overwhelming the quality-control machinery tasked with monitoring and retaining misfolded proteins in the endoplasmic reticulum. This raises the question of whether smallmolecule correctors of K ir1.1 folding and/ or trafficking could provide some therapeutic benefit to Bartter’s syndrome patients
Future Med. Chem. (2014) 6(9), 971–973
part of
ISSN 1756-8919
971
Editorial Denton carrying these mutations. Unfortunately, this class of corrector would probably be ineffective against mixed trafficking/gating mutants, since they remain electrically silent after forced expression in the membrane [3] . Rescuing the function of mixed or strict gating mutants would require a drug that is capable of correcting the underlying gating defect. K ir1.1 gating is normally regulated by intracellular pH (pHi) and the membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2); however, some Bartter’s mutants co-opt these mechanisms and stabilize the channel in the closed state [5,6] . The mechanisms underlying pH- and PIP2-dependent gating converge on a common channel structure, called the ‘helix-bundle gate’ (HBG), which is located near the membrane–cytoplasm interface. Gating transitions appear to involve hydrogen bond reactions between lysine 80 (K80) and alanine 177 (A177) on M1 and M2 membrane helices, respectively [7,8] ; mutation of K80 to methionine (K80M) favors the open state by preventing K80-A177 hydrogen bonding. Furthermore, and importantly, the K80M mutation has been shown to rescue the function of several Bartter’s mutants [4,9] . This raises the intriguing possibility that small molecules capable of opening the HBG will also correct the gating defect underlying Bartter’s syndrome.
“
An important and timely question is whether inward rectifier potassium channels represent viable drug targets for these rare ‘channelopathies’.
”
How would one design an assay of K ir1.1 gating that has sufficient throughput to enable a robust screening effort, and given the genetic heterogeneity of the Bartter’s syndrome, can identify correctors that work on several different Bartter’s mutants? One possibility is to select a representative mutant for assay development and screen for channel potentiators using high-throughput fluorescence assays (e.g., thallium flux [10]) or parallel patchclamp electrophysiology [11,12] . Of course, a potential disadvantage of this approach is that the correctors may only be active against the selected mutant. Therefore, a potentially better approach would be to design an assay around the wild-type channel for openers of the HBG. K ir1.1 is considered a ‘weak rectifier’ due to its high open probability across a broad range of membrane potentials. It may therefore be difficult to identify potentiators of wild-type K ir1.1 without first partially closing the HBG. In principle, there are a few ways this could be done. For example, one could use membrane-permeant acetate buffers or photo-activated ‘caged protons’ to induce intracellular acidification-dependent closure of the HBG and screen for compounds that keep it open. Alternatively, it may be possible to identify compounds
972
Future Med. Chem. (2014) 6(9)
that prevent or reverse HBG closure in response to depletion of membrane PIP2 using, for example, a ligandactivated, PLC-coupled Gaq/11 receptor co-expressed with K ir1.1. Finally, one could potentially design an assay around so-called inactivation gating of K ir1.1 induced by depletion of extracellular K+. Similar to gating by pHi and PIP2, this mechanism also involves the HBG since inactivation can be prevented by the K80M mutation. Pretreating the channel with an extracellular pore blocker such as barium can also prevent inactivation, suggesting that extracellular pore collapse is also involved [13,14] . Whether small-molecule potentiators can prevent inactivation without also blocking the channel remains to be determined. Andersen–Tawil syndrome & Kir2.1 Andersen–Tawil (AT) syndrome is a rare (only ~100 people diagnosed worldwide) autosomal-dominant channelopathy caused by mutations in the classical inward rectifier K ir2.1 (KCNJ2), and is characterized by periodic paralysis, cardiac arrhythmias and dysmorphic features [15] . Current therapies are directed toward treating the associated muscle weakness and cardiac manifestations of the disease [16] . Similar to Bartter’s mutants, AT mutants also exhibit defects in channel trafficking and/or gating [6,17,18] , so many of the same considerations discussed above are applicable to developing small-molecule correctors for K ir2.1. It is notable that Caballero et al. recently showed that the antiarrhythmic agent flecainide potentiates currents through wild-type K ir2.1 by reducing polyamine block of the pore [19] . This apparently involves flecainide interactions with cysteine 311 located in the cytoplasmic domain several angstroms away from the pore lining residues that mediate polyamine binding. Remarkably, overnight flecainide treatment was able to partially restore cell surface expression and function of an AT syndrome mutant, which may explain the therapeutic benefit of flecainide observed in a small cohort of Andersen’s patients [19] . Despite the serious risks inherent in drugging a repolarizing K+ current in the ventricles, this study suggests that it may be at least possible to develop small-molecule K ir2.1 correctors for some AT syndrome mutants. Future perspective With the recent identification of disease mutations in K ir4.1 (SeSAME/EAST syndrome) [20,21] and K ir7.1 (snowflake vitreoretinal degeneration) [22] , it is clearly possible that additional K ir channelopathies will be identified in the future. Fluorescence-based screening platforms that enable high-throughput interrogation of small-molecule libraries have been developed for every sub-class and nearly every sub-family member of the K ir channel family [10–12,23–25; Denton JS, Unpublished Data] .
future science group
Druggability of the inward rectifier family: a hope for rare channelopathies?
The next grand challenges will be configuring these high-throughput screening assays for loss-of-function mutants and, of course, securing funding to do so.
This work was funded by National Institute of Diabetes and Digestive and Kidney Diseases grant 1R01DK082884
(JS Denton). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
References
13 Sackin H, Syn S, Palmer LG, Choe H, Walters D. Regulation
Financial & competing interests disclosure
1
2
3
Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol. Rev. 90(1), 291–366 (2010). Simon DB, Karet FE, Rodriguez-Soriano J et al. Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel, ROMK. Nat. Genet. 14(2), 152–156 (1996). Peters M, Ermert S, Jeck N et al. Classification and rescue of ROMK mutations underlying hyperprostaglandin E syndrome/antenatal Bartter syndrome. Kidney Int. 64(3), 923–932 (2003).
of ROMK by extracellular cations. Biophys. J. 80(2), 683–697 (2001). 14 Sackin H, Vasilyev A, Palmer LG, Krambis M. Permeant
cations and blockers modulate pH gating of ROMK channels. Biophys. J. 84(2 Pt 1), 910–921 (2003). 15 Plaster Nm, Tawil R, Tristani-Firouzi M et al. Mutations in
K ir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 105(4), 511–519 (2001). 16 Sansone V, Tawil R. Management and treatment of
Andersen–Tawil syndrome (ATS). Neurotherapeutics 4(2), 233–237 (2007).
4
Fallen K, Banerjee S, Sheehan J et al. The K ir channel immunoglobulin domain is essential for K ir1.1 (ROMK) thermodynamic stability, trafficking and gating. Channels (Austin) 3(1), 57–68 (2009).
17 Bendahhou S, Donaldson MR, Plaster NM, Tristani-Firouzi
5
Schulte U, Fakler B. Gating of inward-rectifier K+ channels by intracellular pH. Eur. J. Biochem. 267(19), 5837–5841 (2000).
18 Ballester LY, Benson DW, Wong B et al. Trafficking-
6
Lopes Cm, Zhang H, Rohacs T, Jin T, Yang J, Logothetis DE. Alterations in conserved K ir channel-PIP2 interactions underlie channelopathies. Neuron 34(6), 933–944 (2002).
19 Caballero R, Dolz-Gaiton P, Gomez R et al. Flecainide
7
Rapedius M, Haider S, Browne KF et al. Structural and functional analysis of the putative pH sensor in the K ir1.1 (ROMK) potassium channel. EMBO Rep. 7(6), 611–616 (2006).
8
9
Rapedius M, Fowler PW, Shang L, Sansom MS, Tucker SJ, Baukrowitz T. H bonding at the helix-bundle crossing controls gating in K ir potassium channels. Neuron 55(4), 602–614 (2007). Leng Q, Macgregor GG, Dong K, Giebisch G, Hebert SC. Subunit-subunit interactions are critical for proton sensitivity of ROMK: evidence in support of an intermolecular gating mechanism. Proc. Natl Acad. Sci. USA 103(6), 1982–1987 (2006).
10 Raphemot R, Weaver CD, Denton JS. High-throughput
screening for small-molecule modulators of inward rectifier potassium channels. J. Vis. Exp. 71, 4209 (2013). 11 Raphemot R, Kadakia RJ, Olsen ML et al. Development and
validation of fluorescence-based and automated patch clamp-based functional assays for the inward rectifier potassium channel k ir4.1. Assay Drug Dev. Technol. 11(9–10), 532–543 (2013). 12 Bhave G, Chauder Ba, Liu W et al. Development of a
selective small-molecule inhibitor of K ir1.1, the renal outer medullary potassium channel. Mol. Pharmacol. 79(1), 42–50 (2011).
future science group
Editorial
M, Fu YH, Ptacek LJ. Defective potassium channel K ir2.1 trafficking underlies Andersen–Tawil syndrome. J. Biol. Chem. 278(51), 51779–51785 (2003). competent and trafficking-defective KCNJ2 mutations in Andersen syndrome. Hum. Mutat. 27(4), 388 (2006). increases K ir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification. Proc. Natl Acad. Sci. USA 107(35), 15631–15636 (2010). 20 Scholl UI, Choi M, Liu T et al. Seizures, sensorineural
deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. Proc. Natl Acad. Sci. USA 106(14), 5842–5847 (2009). 21 Bockenhauer D, Feather S, Stanescu HC et al. Epilepsy,
ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N. Engl. J. Med. 360(19), 1960–1970 (2009). 22 Hejtmancik JF, Jiao X, Li A et al. Mutations in KCNJ13 cause
autosomal-dominant snowflake vitreoretinal degeneration. Am. J. Hum. Genet. 82(1), 174–180 (2008). 23 Lewis LM, Bhave G, Chauder BA et al. High-throughput
screening reveals a small-molecule inhibitor of the renal outer medullary potassium channel and K ir7.1. Mol. Pharmacol. 76(5), 1094–1103 (2009). 24 Raphemot R, Lonergan DF, Nguyen TT et al. Discovery,
characterization, and structure-activity relationships of an inhibitor of inward rectifier potassium (K ir) channels with preference for k ir2.3, k ir3.x, and k ir7.1. Front. Pharmacol. 2, 75 (2011). 25 Niswender CM, Johnson KA, Luo Q et al. A novel assay of
Gi/o-linked G protein-coupled receptor coupling to potassium channels provides new insights into the pharmacology of the group III metabotropic glutamate receptors. Mol. Pharmacol. 73(4), 1213–1224 (2008).
www.future-science.com
973
Editorial Special Focus Issue: Rare Diseases
Medicinal Chemistry
For reprint orders, please contact [email protected]
Druggability of the inward rectifier family: a hope for rare channelopathies? “
With the recent identification of disease mutations in Kir4.1 (SeSAME/EAST syndrome) and Kir7.1 (snowflake vitreoretinal degeneration), it is clearly possible that additional Kir channelopathies will be identified in the future.
”
Keywords: arrhythmia • gating • heart • helix-bundle crossing • hypertension • hypotension • kidney • nephron • trafficking • rare diseases
The inward rectifier potassium (K ir) channel family is made up of 16 genes (KCNJx) encoding seven sub-families (K ir1–K ir7) of structurally related protein subunits. K ir channels are tetramers of identical (homomeric) or different (heteromeric) subunits, each possessing two transmembrane domains (M1 and M2), a pore loop, and a large cytoplasmic domain. The term ‘inward rectification’ refers to their preference for passing K+ current in the inward direction due to pore block of outward current by intracellular polyamines. K ir channels are pivotal regulators of electrical excitability in neurons and cardiomyocytes and mediate K+ transport in epithelial cells of the kidney tubule. Their importance in humans is underscored by the existence of rare, monogenic diseases caused by mutations in K ir channel-encoding genes [1] . With the emergence of enabling techno logies for K ir channel-directed drug discovery in pharmaceutical and academic laboratories, an important and timely question is whether K ir channels represent viable drug targets for these rare ‘channelopathies’. Bartter’s syndrome & Kir1.1 The life-threatening kidney disease, antenatal (type II) Bartter’s syndrome, is an autosomal recessive disorder caused by loss-of-function mutations in KCNJ1 [2] , which encodes the founding K ir1 channel family member K ir1.1 (also called the renal outer medullary K+ channel). Bartter’s syndrome presents early in life with polyhydramnios, preterm birth, failure to thrive, and chronic kidney dysfunction
10.4155/FMC.14.12 © 2014 Future Science Ltd
characterized by polyuria, low blood pressure, hypokalemia and metabolic alkalosis. Excessive urination results from a loss of NaCl reabsorption in the thick ascending limb of Henle’s loop and osmotically coupled water reabsorption in the distal nephron, both of which are dependent on K ir1.1 function in the thick ascending limb. Current treatments include cyclooxygenase inhibitors and potassium-sparing diuretics to limit urinary sodium and potassium loss, respectively. With a prevalence of 1 in 1,000,000 and more than 30 distinct mutations identified thus far, antenatal Bartter’s syndrome is both rare and genetically heterogeneous [2] . In general, Bartter’s mutations inhibit K ir1.1 function by:
Jerod S Denton Department of Anesthesiology, Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232, USA jerod.s.denton@vanderbilt. edu
• Impairing the biogenesis and trafficking of the channel to the cell surface; • Disrupting conformational ‘gating’ chan ges that enable channel opening; • A combination of both [3,4] . At least in heterologous expression systems, some trafficking mutants can be forced to the cell surface and functionally rescued by overexpression, presumably by overwhelming the quality-control machinery tasked with monitoring and retaining misfolded proteins in the endoplasmic reticulum. This raises the question of whether smallmolecule correctors of K ir1.1 folding and/ or trafficking could provide some therapeutic benefit to Bartter’s syndrome patients
Future Med. Chem. (2014) 6(9), 971–973
part of
ISSN 1756-8919
971
Editorial Denton carrying these mutations. Unfortunately, this class of corrector would probably be ineffective against mixed trafficking/gating mutants, since they remain electrically silent after forced expression in the membrane [3] . Rescuing the function of mixed or strict gating mutants would require a drug that is capable of correcting the underlying gating defect. K ir1.1 gating is normally regulated by intracellular pH (pHi) and the membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2); however, some Bartter’s mutants co-opt these mechanisms and stabilize the channel in the closed state [5,6] . The mechanisms underlying pH- and PIP2-dependent gating converge on a common channel structure, called the ‘helix-bundle gate’ (HBG), which is located near the membrane–cytoplasm interface. Gating transitions appear to involve hydrogen bond reactions between lysine 80 (K80) and alanine 177 (A177) on M1 and M2 membrane helices, respectively [7,8] ; mutation of K80 to methionine (K80M) favors the open state by preventing K80-A177 hydrogen bonding. Furthermore, and importantly, the K80M mutation has been shown to rescue the function of several Bartter’s mutants [4,9] . This raises the intriguing possibility that small molecules capable of opening the HBG will also correct the gating defect underlying Bartter’s syndrome.
“
An important and timely question is whether inward rectifier potassium channels represent viable drug targets for these rare ‘channelopathies’.
”
How would one design an assay of K ir1.1 gating that has sufficient throughput to enable a robust screening effort, and given the genetic heterogeneity of the Bartter’s syndrome, can identify correctors that work on several different Bartter’s mutants? One possibility is to select a representative mutant for assay development and screen for channel potentiators using high-throughput fluorescence assays (e.g., thallium flux [10]) or parallel patchclamp electrophysiology [11,12] . Of course, a potential disadvantage of this approach is that the correctors may only be active against the selected mutant. Therefore, a potentially better approach would be to design an assay around the wild-type channel for openers of the HBG. K ir1.1 is considered a ‘weak rectifier’ due to its high open probability across a broad range of membrane potentials. It may therefore be difficult to identify potentiators of wild-type K ir1.1 without first partially closing the HBG. In principle, there are a few ways this could be done. For example, one could use membrane-permeant acetate buffers or photo-activated ‘caged protons’ to induce intracellular acidification-dependent closure of the HBG and screen for compounds that keep it open. Alternatively, it may be possible to identify compounds
972
Future Med. Chem. (2014) 6(9)
that prevent or reverse HBG closure in response to depletion of membrane PIP2 using, for example, a ligandactivated, PLC-coupled Gaq/11 receptor co-expressed with K ir1.1. Finally, one could potentially design an assay around so-called inactivation gating of K ir1.1 induced by depletion of extracellular K+. Similar to gating by pHi and PIP2, this mechanism also involves the HBG since inactivation can be prevented by the K80M mutation. Pretreating the channel with an extracellular pore blocker such as barium can also prevent inactivation, suggesting that extracellular pore collapse is also involved [13,14] . Whether small-molecule potentiators can prevent inactivation without also blocking the channel remains to be determined. Andersen–Tawil syndrome & Kir2.1 Andersen–Tawil (AT) syndrome is a rare (only ~100 people diagnosed worldwide) autosomal-dominant channelopathy caused by mutations in the classical inward rectifier K ir2.1 (KCNJ2), and is characterized by periodic paralysis, cardiac arrhythmias and dysmorphic features [15] . Current therapies are directed toward treating the associated muscle weakness and cardiac manifestations of the disease [16] . Similar to Bartter’s mutants, AT mutants also exhibit defects in channel trafficking and/or gating [6,17,18] , so many of the same considerations discussed above are applicable to developing small-molecule correctors for K ir2.1. It is notable that Caballero et al. recently showed that the antiarrhythmic agent flecainide potentiates currents through wild-type K ir2.1 by reducing polyamine block of the pore [19] . This apparently involves flecainide interactions with cysteine 311 located in the cytoplasmic domain several angstroms away from the pore lining residues that mediate polyamine binding. Remarkably, overnight flecainide treatment was able to partially restore cell surface expression and function of an AT syndrome mutant, which may explain the therapeutic benefit of flecainide observed in a small cohort of Andersen’s patients [19] . Despite the serious risks inherent in drugging a repolarizing K+ current in the ventricles, this study suggests that it may be at least possible to develop small-molecule K ir2.1 correctors for some AT syndrome mutants. Future perspective With the recent identification of disease mutations in K ir4.1 (SeSAME/EAST syndrome) [20,21] and K ir7.1 (snowflake vitreoretinal degeneration) [22] , it is clearly possible that additional K ir channelopathies will be identified in the future. Fluorescence-based screening platforms that enable high-throughput interrogation of small-molecule libraries have been developed for every sub-class and nearly every sub-family member of the K ir channel family [10–12,23–25; Denton JS, Unpublished Data] .
future science group
Druggability of the inward rectifier family: a hope for rare channelopathies?
The next grand challenges will be configuring these high-throughput screening assays for loss-of-function mutants and, of course, securing funding to do so.
This work was funded by National Institute of Diabetes and Digestive and Kidney Diseases grant 1R01DK082884
(JS Denton). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
References
13 Sackin H, Syn S, Palmer LG, Choe H, Walters D. Regulation
Financial & competing interests disclosure
1
2
3
Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol. Rev. 90(1), 291–366 (2010). Simon DB, Karet FE, Rodriguez-Soriano J et al. Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel, ROMK. Nat. Genet. 14(2), 152–156 (1996). Peters M, Ermert S, Jeck N et al. Classification and rescue of ROMK mutations underlying hyperprostaglandin E syndrome/antenatal Bartter syndrome. Kidney Int. 64(3), 923–932 (2003).
of ROMK by extracellular cations. Biophys. J. 80(2), 683–697 (2001). 14 Sackin H, Vasilyev A, Palmer LG, Krambis M. Permeant
cations and blockers modulate pH gating of ROMK channels. Biophys. J. 84(2 Pt 1), 910–921 (2003). 15 Plaster Nm, Tawil R, Tristani-Firouzi M et al. Mutations in
K ir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 105(4), 511–519 (2001). 16 Sansone V, Tawil R. Management and treatment of
Andersen–Tawil syndrome (ATS). Neurotherapeutics 4(2), 233–237 (2007).
4
Fallen K, Banerjee S, Sheehan J et al. The K ir channel immunoglobulin domain is essential for K ir1.1 (ROMK) thermodynamic stability, trafficking and gating. Channels (Austin) 3(1), 57–68 (2009).
17 Bendahhou S, Donaldson MR, Plaster NM, Tristani-Firouzi
5
Schulte U, Fakler B. Gating of inward-rectifier K+ channels by intracellular pH. Eur. J. Biochem. 267(19), 5837–5841 (2000).
18 Ballester LY, Benson DW, Wong B et al. Trafficking-
6
Lopes Cm, Zhang H, Rohacs T, Jin T, Yang J, Logothetis DE. Alterations in conserved K ir channel-PIP2 interactions underlie channelopathies. Neuron 34(6), 933–944 (2002).
19 Caballero R, Dolz-Gaiton P, Gomez R et al. Flecainide
7
Rapedius M, Haider S, Browne KF et al. Structural and functional analysis of the putative pH sensor in the K ir1.1 (ROMK) potassium channel. EMBO Rep. 7(6), 611–616 (2006).
8
9
Rapedius M, Fowler PW, Shang L, Sansom MS, Tucker SJ, Baukrowitz T. H bonding at the helix-bundle crossing controls gating in K ir potassium channels. Neuron 55(4), 602–614 (2007). Leng Q, Macgregor GG, Dong K, Giebisch G, Hebert SC. Subunit-subunit interactions are critical for proton sensitivity of ROMK: evidence in support of an intermolecular gating mechanism. Proc. Natl Acad. Sci. USA 103(6), 1982–1987 (2006).
10 Raphemot R, Weaver CD, Denton JS. High-throughput
screening for small-molecule modulators of inward rectifier potassium channels. J. Vis. Exp. 71, 4209 (2013). 11 Raphemot R, Kadakia RJ, Olsen ML et al. Development and
validation of fluorescence-based and automated patch clamp-based functional assays for the inward rectifier potassium channel k ir4.1. Assay Drug Dev. Technol. 11(9–10), 532–543 (2013). 12 Bhave G, Chauder Ba, Liu W et al. Development of a
selective small-molecule inhibitor of K ir1.1, the renal outer medullary potassium channel. Mol. Pharmacol. 79(1), 42–50 (2011).
future science group
Editorial
M, Fu YH, Ptacek LJ. Defective potassium channel K ir2.1 trafficking underlies Andersen–Tawil syndrome. J. Biol. Chem. 278(51), 51779–51785 (2003). competent and trafficking-defective KCNJ2 mutations in Andersen syndrome. Hum. Mutat. 27(4), 388 (2006). increases K ir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification. Proc. Natl Acad. Sci. USA 107(35), 15631–15636 (2010). 20 Scholl UI, Choi M, Liu T et al. Seizures, sensorineural
deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. Proc. Natl Acad. Sci. USA 106(14), 5842–5847 (2009). 21 Bockenhauer D, Feather S, Stanescu HC et al. Epilepsy,
ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N. Engl. J. Med. 360(19), 1960–1970 (2009). 22 Hejtmancik JF, Jiao X, Li A et al. Mutations in KCNJ13 cause
autosomal-dominant snowflake vitreoretinal degeneration. Am. J. Hum. Genet. 82(1), 174–180 (2008). 23 Lewis LM, Bhave G, Chauder BA et al. High-throughput
screening reveals a small-molecule inhibitor of the renal outer medullary potassium channel and K ir7.1. Mol. Pharmacol. 76(5), 1094–1103 (2009). 24 Raphemot R, Lonergan DF, Nguyen TT et al. Discovery,
characterization, and structure-activity relationships of an inhibitor of inward rectifier potassium (K ir) channels with preference for k ir2.3, k ir3.x, and k ir7.1. Front. Pharmacol. 2, 75 (2011). 25 Niswender CM, Johnson KA, Luo Q et al. A novel assay of
Gi/o-linked G protein-coupled receptor coupling to potassium channels provides new insights into the pharmacology of the group III metabotropic glutamate receptors. Mol. Pharmacol. 73(4), 1213–1224 (2008).
www.future-science.com
973
