Potassium Channels in Pancreatic Cancer

Potassium channels in pancreatic cancer

Authors: Abstract

Mikio Hayashi Pancreatic duct adenocarcinoma accounts for Department of Physiology, approximately 90% of pancreatic cancers and has a Kansai Medical University, 5-1 very poor prognosis. Several K+ channels have Shimmachi 2, Hirakata, Osaka been suggested as hallmarks for adenocarcinoma. 573-1010, Japan. This review focuses on molecular candidates of E-mail: + [email protected] functional K channels in pancreatic

adenocarcinoma, including KCNN4 (KCa3.1), Hiroko Matsuda KCNJ3 (Kir3.1), KCNA3 (Kv1.3), KCNA5 (Kv1.5), Department of Physiology, KCNH1 (K 10.1), and KCNK5 (K 5.1). We Kansai Medical University, 5-1 v 2P + Shimmachi 2, Hirakata, Osaka provide an overview of K channels with respect to 573-1010, Japan. their electrophysiological and pharmacological E-mail: characteristics and tissue expression, in addition to [email protected] their identification and functions in pancreatic

Corresponding Author: adenocarcinomas. We conclude by discussing some Mikio Hayashi, PhD outstanding questions and future directions in Tel. +81-72-804-2321 pancreatic K+ channel research with respect to the Fax: +81-72-804-2329 treatment of pancreatic cancer. E-mail: [email protected] Keywords: cancer, EAG1, GIRK1, pancreas, SK4, TASK-2. Conflicts of interst: None declared. Abbreviations: No funding was provided for EC50, half maximal effective concentration; HERG, this research. human ether-à-go-go related gene; Kd, dissociation

constant; Ki, inhibitory constant; PKC, protein

kinase C; V1/2, half-maximal voltage.

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1. Introduction present in every cell. They set the cell membrane potential and thereby regulate Pancreatic duct adenocarcinoma the excitability of neurons and myocytes accounts for approximately 90% of as well as the transport of ions and water pancreatic cancers and has a very poor in epithelia. Duct epithelial cells in the prognosis. As reported in the World – pancreas secrete a HCO3 -rich pancreatic Cancer Report 2014 by the World Health juice that neutralizes acid chyme in the Organization, 25% of patients survive for duodenum. K+ channels are clearly one year and 5% for five years after being important for setting the resting diagnosed. Surgical resection of the membrane potential and providing the primary tumor remains the only option for driving force for anion exit and fluid long-term survival; however, candidates secretion in the epithelium [27, 28, 72]. for this surgery represent a very low Several K+ channels have been suggested percentage of all patients. as hallmarks for cancer, including Chemotherapy and radiation therapy are pancreatic duct adenocarcinoma [63]. frequently insufficient and controversial for the treatment of inoperable patients. It currently remains unknown + Thus, novel molecular targets for the whether many of the K channels development of alternative therapies are identified to date are functional in urgently required [31, 59]. pancreatic duct adenocarcinoma, and if they have potential as molecular targets Ion channels have been associated for therapies. The aim of this review is with the malignant phenotype of cancer to provide an overview of K+ channels cells and contribute to virtually all basic with respect to their electrophysiological cellular processes, including their crucial and pharmacological characteristics as roles in maintaining tissue homeostasis well as tissue expression. We also address such as proliferation, differentiation, and some outstanding questions and future apoptosis [60]. Potassium (K+) channels directions in the development of cancer are important membrane proteins that are therapies.

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2. KCNN4 (KCa3.1, SK4) charybdotoxin (2–28 nM), TRAM-34 (20

2.1. Expression and function nM), and clotrimazole (25–150 nM) [9, 32,

35, 76, 81, 82]. KCa3.1 currents were also KCNN4 coding for the KCa3.1 activated by DC-EBIO (Kd value of 0.8 protein was cloned from the placenta and μM) and 1-EBIO (15–84 μM) [35, 68, 76, pancreas [32, 39]. The functional 81]. expression of the KCNN4 gene has been detected in erythrocytes [61], T 2.3. Expression in cancer lymphocytes [5], microglia [40], airway Electrophysiological studies epithelial cells [2], and pancreatic ducts demonstrated the functional expression of

[28, 29, 77]. Single-channel openings KCa3.1 in BxPC-3 and MiaPaCa-2 human have been observed at positive and pancreatic carcinoma cell lines. The negative membrane potentials, and gating functional expression of KCa3.1 channels showed no significant voltage dependency. in BxPC-3 and MiaPaCa-2 cells was 3- to The single-channel current–voltage 6-fold higher than that in the Panc-1 relationship showed weak inward pancreatic cancer cell line. KCa3.1 currents rectification with conductance of 30–54 were inhibited by charybdotoxin, pS in heterologous expression systems [32, clotrimazole, and TRAM-34 with Ki

35, 76]. KCa3.1 channels were shown to be values of 10 nM, 40 nM, and 20 nM, activated by intracellular Ca2+ respectively. The proliferation of BxPC-3 concentrations with EC50 values of and MiaPaCa-2 was completely inhibited 0.1–0.3 μM [32, 39, 76, 81]. In addition, by 10 μM clotrimazole or TRAM-34.

KCa3.1 channels were regulated by KCNN4 mRNA levels in BxPC-3 and cAMP/cAMP-dependent protein kinase MiaPaCa-2 cells were 3- to 8-fold higher signaling pathway [19, 26, 61]. than those in Panc-1, corresponding to the

2.2. Pharmacology values obtained in electrophysiological analyses. Eight out of 9 samples (89%) of KCa3.1 currents were inhibited by primary pancreatic tumors were found to maurotoxin (Ki value of 1 nM), contain 6- to 66-fold higher levels of

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KCNN4 mRNA [34]. KCa3.1 channel conductance of 35–42 pS in heterologous immunoreactivity was shown to be expression systems [46, 47]. Kir3.1 localized in the basolateral and luminal channels were previously reported to be membranes in a monolayer of Capan-1, a activated by G protein βγ subunits [64]. human pancreas adenocarcinoma cell line; 3.2. Pharmacology however, its expression appeared to be Kir3.1/Kir3.x currents were inhibited stronger in the luminal membrane. by tertiapin (Ki value of 8 nM), Consistent with this finding, the tertiapin-Q (13 nM), pimozide (2–3 μM), short-circuit current of the Capan-1 cell fluoxetine (7 μM), sertraline (12 μM), monolayer was enhanced by the KCa3.1 duloxetine (15–17 μM), clomipramine channel activator DC-EBIO (100 μM) in (18–24 μM), and amoxapine (18–38 μM) luminal or basolateral bathing solution [28, [37, 38, 42–45]. 77]. 3.3. Expression in cancer

3. KCNJ3 (Kir3.1, GIRK1) Kir3.1 immunoreactivity was shown 3.1. Expression and function to be localized in the apical cytoplasm in

KCNJ3 coding for the Kir3.1 protein epithelial cells of the normal pancreas and was isolated from the heart cDNA library tumor cells of adenocarcinomas. The

[47]. The Kir3.1 protein is generally expression of Kir3.1 was stronger in incorporated into heteromers with other adenocarcinomas than in normal tissue.

Kir3.x subunits in order to form functional Consistent with this histochemical channels in native cells and tissues [46]. evaluation, KCNJ3 mRNA levels were The functional expression of the KCNJ3 8-fold higher in pancreatic adeno- gene has been detected in the heart [46], carcinomas than in normal tissue. brain [50], pituitary gland [55], and However, no correlation was observed endocrine pancreas [33]. The single- between Kir3.1 expression and metastasis channel current–voltage relationship [7]. showed inward rectification with

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4. KCNA3 (Kv1.3) CP339818 (150 nM), and UK78282 (200

4.1. Expression and function nM) [11, 24, 25, 83]. 4.3. Expression in cancer KCNA3 coding for the Kv1.3 protein was isolated from the cortex and T Kv1.3 immunoreactivity was shown lymphocyte cDNA library [3, 74]. The to be localized in the cytoplasm in functional expression of the KCNA3 gene epithelial cells of the normal pancreas. has been detected in the cortex [74], T The expression of Kv1.3 was weaker in lymphocytes [3, 23], and oligodendrocytes adenocarcinomas than in normal tissue [6,

[12]. Kv1.3 currents were activated at 7]. Additionally, KCNA3 mRNA levels voltages more positive than −50 mV and were slightly decreased in pancreatic

V1/2 was −35 mV [23]. Single-channel cancer. The weak expression of Kv1.3 was conductance was 13 pS in heterologous associated with metastasis to local lymph expression systems [23]. Native Kv1.3 nodes and/or distant organs [7]. channels were up-regulated by PKC 5. KCNA5 (Kv1.5) phosphorylation in lymphocytes, whereas they were down-regulated by cAMP/PKA 5.1. Expression and function signaling [13, 48]. KCNA5 coding for the Kv1.5 protein

4.2. Pharmacology was isolated from the brain cDNA library [75]. The functional expression of the Kv1.3 currents were inhibited by KCNA5 gene has been detected in skeletal ADWX-1 (Ki value of 2 pM), ShK (11 and cardiac muscles [54, 70] and islets pM), HsTx1 (12 pM), BmKTX-D33H (15 [62]. Kv1.5 currents were activated at pM), Pi2 (50 pM), ShK-Dap22 (52 pM), voltages more positive than −30 mV and margatoxin (110 pM), agitoxin-1 (200 V1/2 was −13 mV [54, 70]. Single- pM), Pi3 (500 pM), kaliotoxin (650 pM), channel conductance was 8 pS in naltrexone (1 nM), charybdotoxin (3 nM), heterologous expression systems [54]. Pi1 (11 nM), BgK (39 nM), correolide (90 The activation of PKC and AMP-activated nM), sulfamidbenzamidoindane (100 nM), protein kinase reduced the surface

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expression of Kv1.5 channels [1]. brain [52] and myoblasts [58]. Kv10.1

5.2. Pharmacology currents were activated at voltages more

positive than −50 mV and V1/2 was −4 mV Kv1.5 currents were inhibited by [58]. Single-channel conductance was 8 S9947 (Ki value of 420–700 nM), MSD-D pS in heterologous expression systems (500 nM), clofilium (840 nM), ICAGEN [71]. Intracellular cAMP increased Kv10.1 (1.6 μM), carvedilol (2.6 μM), currents in heterologous expression bupivacaine (4 μM), propafenone (4 μM), systems [8]. In contrast, Kv10.1 channels quinidine (6 μM), and trimethylapigenin were inhibited by intracellular Ca2+ with a (6 μM) [4, 16, 17, 24, 36, 51, 53, 69, 73]. Ki value of 67 nM in the presence of 5.3. Expression in cancer calmodulin [67, 71].

Kv1.5 immunoreactivity was 6.2. Pharmacology moderate in acinar cells, whereas its Kv10.1 currents were inhibited by expression was markedly stronger in astemizole (Ki value of 200 nM), adenocarcinomas surrounding pancreatic mibefradil (1.3 μM), quinidine (1.4 μM), ducts. In some cases, this increase was and imipramine (2 μM) [18, 20, 66]. due to the presence of infiltrating inflammatory cells. Additionally, KCNA5 6.3. Expression in cancer mRNA levels were higher in Kv10.1 immunoreactivity was adenocarcinomas than in normal tissue detected in pancreatic acini, while 6 out of [6]. 8 pancreatic carcinoma samples stained

positive [30]. A specific monoclonal 6. KCNH1 (Kv10.1, EAG1) Kv10.1 antibody (mAb56) reduced tumor 6.1. Expression and function growth by BxPC3, a human pancreas

KCNH1 coding for the Kv10.1 adenocarcinoma cell line. This antibody protein was isolated from the brain cDNA inhibited Kv10.1 currents with a Ki value library [79]. The functional expression of of 73 nM. However, it (300 nM) did not the KCNH1 gene has been detected in the affect the HERG current, the inhibition of

Medical Research Archives, Vol. 4, Issue 4, August 2016 Potassium channels in pancreatic cancer which triggers dangerous cardiac and chloroform, which are volatile consequences [21]. anesthetics [22].

7.3. Expression in cancer 7. KCNK5 (K2P5.1, TASK-2)

7.1. Expression and function An electrophysiological study indicated that TASK-2 was expressed in KCNK5 coding for the K2P5.1 HPAF, a human pancreatic ductal protein was isolated from the brain cDNA adenocarcinoma cell line [15]. library [65]. The functional expression of Clofilium-sensitive K+ conductance, K2P5.1 has been detected in retrotrapezoid possibly K2P5.1, was located in the nucleus chemoreceptor neurons [78], luminal membrane of a monolayer of cochlear outer sulcus cells [10], and HPAF. However, its contribution to cancer kidney proximal convoluted tubule cells progression is still unknown. [80]. K2P5.1 channels have an intermediate conductance of 50–78 pS [14, 49, 8. Concluding remarks

65]. K2P5.1 is sensitive to extracellular pH This review described the current in the physiological range, with a pKa status on the molecular basis for a number value of 7.5–8.3 [22, 56, 57, 65]. of K+ channels found in pancreatic Activators of PKC were previously shown adenocarcinomas and cell lines. Molecular to potentiate K2P5.1 currents in Xenopus biological and immunohistochemcal oocytes [22]. The K2P5.1 channel is also studies demonstrated how some of these osmosensitive and participates in cell K+ channels contribute to volume regulation [57]. pathophysiological processes in cancer 7.2. Pharmacology progression. Future studies are needed in order to verify functional K+ channels in K2P5.1 currents were inhibited by primary pancreatic tumors and affirm their quinine (Ki value of 22 μM), clofilium (25 μM), bupivacaine (26 μM), and pathophysiological functions in malignant growth, the evasion of apoptosis, and ropivacaine (95 μM) [41, 57, 65]. K2P5.1 was activated by halothane, isoflurane, metastasis [63]. Our knowledge on the

Medical Research Archives, Vol. 4, Issue 4, August 2016 Potassium channels in pancreatic cancer roles of K+ channels in the malignant on pancreatic adenocarcinoma foreshadow phenotype of pancreatic adenocarcinomas similar trends; thus, more information is remains limited. Some ion channels are needed in this area before specific K+ now being regarded as hallmarks for channel molecules may be targeted for the cancer progression and emerging studies treatment of pancreatic cancer.

Medical Research Archives, Vol. 4, Issue 4, August 2016 Potassium channels in pancreatic cancer

References

+ 1. Andersen MN, Skibsbye L, Tang C, T lymphocyte K channels ameliorates Petersen F, MacAulay N, Rasmussen experimental autoimmune HB, et al. PKC and AMPK regulation encephalomyelitis, a model for of Kv1.5 potassium channels. Channels multiple sclerosis. Proc Natl Acad Sci (Austin) 2015; 9:121-8. U S A 2001; 98:13942-7. doi:10.1080/19336950.2015.1036205 doi:10.1073/pnas.241497298

2. Arthur GK, Duffy SM, Roach KM, 6. Bielanska J, Hernández-Losa J, Hirst RA, Shikotra A, Gaillard EA, et Pérez-Verdaguer M, Moline T, Somoza + R, Ramón YCS, et al. al. KCa3.1 K channel expression and function in human bronchial epithelial Voltage-dependent potassium channels cells. PLoS One 2015; 10:e0145259. Kv1.3 and Kv1.5 in human cancer. doi:10.1371/journal.pone.0145259 Curr Cancer Drug Targets 2009; 9:904-14. 3. Attali B, Romey G, Honoré E, doi:10.2174/156800909790192400 Schmid-Alliana A, Mattéi MG, Lesage F, et al. Cloning, functional expression, 7. Brevet M, Fucks D, Chatelain D, and regulation of two K+ channels in Regimbeau JM, Delcenserie R, human T lymphocytes. J Biol Chem Sevestre H, et al. Deregulation of 2 1992; 267:8650-7. PMID:1373731 potassium channels in pancreas adenocarcinomas: implication of Kv1.3 4. Bachmann A, Gutcher I, Kopp K, gene promoter methylation. Pancreas Brendel J, Bosch RF, Busch AE, et al. 2009; 38:649-54. Characterization of a novel Kv1.5 doi:10.1097/MPA.0b013e3181a56ebf channel blocker in Xenopus oocytes, 8. Brüggemann A, Pardo LA, Stühmer W, CHO cells, human and rat cardiomyocytes. Naunyn Pongs O. Ether-à-go-go encodes a + Schmiedebergs Arch Pharmacol 2001; voltage-gated channel permeable to K 2+ 364:472-8. and Ca and modulated by cAMP. doi:10.1007/s002100100474 Nature 1993; 365:445-8. doi:10.1038/365445a0 5. Beeton C, Wulff H, Barbaria J, Clot-Faybesse O, Pennington M, 9. Castle NA, London DO, Creech C, Bernard D, et al. Selective blockade of Fajloun Z, Stocker JW, Sabatier JM.

Medical Research Archives, Vol. 4, Issue 4, August 2016 Potassium channels in pancreatic cancer

Maurotoxin: a potent inhibitor of doi:10.1007/s002329900189

intermediate conductance 14. Cotten JF, Zou HL, Liu C, Au JD, Yost 2+ Ca -activated potassium channels. CS. Identification of native rat Mol Pharmacol 2003; 63:409-18. cerebellar granule cell currents due to doi:10.1124/mol.63.2.409 background K channel KCNK5 10. Cazals Y, Bévengut M, Zanella S, (TASK-2). Brain Res Mol Brain Res Brocard F, Barhanin J, Gestreau C. 2004; 128:112-20. KCNK5 channels mostly expressed in doi:10.1016/j.molbrainres.2004.06.007

cochlear outer sulcus cells are 15. Fong P, Argent BE, Guggino WB, indispensable for hearing. Nat Gray MA. Characterization of vectorial Commun 2015; 6:8780. chloride transport pathways in the doi:10.1038/ncomms9780 human pancreatic duct adenocarcinoma 11. Chandy KG, Cahalan M, Pennington M, cell line HPAF. Am J Physiol Cell Norton RS, Wulff H, Gutman GA. Physiol 2003; 285:C433-45. Potassium channels in T lymphocytes: doi:10.1152/ajpcell.00509.2002

toxins to therapeutic immune- 16. Franqueza L, Longobardo M, Vicente J, suppressants. Toxicon 2001; Delpón E, Tamkun MM, Tamargo J, et 39:1269-76. al. Molecular determinants of doi:10.1016/S0041-0101(01)00120-9 stereoselective bupivacaine block of 12. Chittajallu R, Chen Y, Wang H, Yuan hKv1.5 channels. Circ Res 1997; X, Ghiani CA, Heckman T, et al. 81:1053-64. Regulation of Kv1 subunit expression doi:10.1161/01.RES.81.6.1053

in oligodendrocyte progenitor cells and 17. Franqueza L, Valenzuela C, Delpón E, their role in G1/S phase progression of Longobardo M, Caballero R, Tamargo the cell cycle. Proc Natl Acad Sci U S J. Effects of propafenone and A 2002; 99:2350-5. 5-hydroxy-propafenone on hKv1.5 doi:10.1073/pnas.042698399 channels. Br J Pharmacol 1998; 13. Chung I, Schlichter LC. Native Kv1.3 125:969-78. channels are upregulated by protein doi:10.1038/sj.bjc.0702129

kinase C. J Membr Biol 1997; 18. García-Ferreiro RE, Kerschensteiner D, 156:73-85. Major F, Monje F, Stühmer W, Pardo

Medical Research Archives, Vol. 4, Issue 4, August 2016 Potassium channels in pancreatic cancer

LA. Mechanism of block of hEag1 K+ et al. Expression and chromosomal channels by imipramine and astemizole. localization of a lymphocyte K+ J Gen Physiol 2004; 124:301-17. channel gene. Proc Natl Acad Sci U S doi:10.1085/jgp.200409041 A 1990; 87:9411-5. PMID:2251283

19. Gerlach AC, Gangopadhyay NN, 24. Grissmer S, Nguyen AN, Aiyar J, Devor DC. Kinase-dependent Hanson DC, Mather RJ, Gutman GA, regulation of the intermediate et al. Pharmacological characterization conductance, calcium-dependent of five cloned voltage-gated K+ potassium channel, hIK1. J Biol Chem channels, types Kv1.1, 1.2, 1.3, 1.5, 2000; 275:585-98. and 3.1, stably expressed in doi:10.1074/jbc.275.1.585 mammalian cell lines. Mol Pharmacol

20. Gomez-Lagunas F, Carrillo E, Pardo 1994; 45:1227-34. PMID:7517498 LA, Stühmer W. Gating Modulation of 25. Han S, Yi H, Yin SJ, Chen ZY, Liu H, the Tumor-Related Kv10.1 Channel by Cao ZJ, et al. Structural basis of a Mibefradil. J Cell Physiol 2016. potent peptide inhibitor designed for doi:10.1002/jcp.25448. Kv1.3 channel, a therapeutic target of

21. Gómez-Varela D, Zwick-Wallasch E, autoimmune disease. J Biol Chem Knötgen H, Sánchez A, Hettmann T, 2008; 283:19058-65. doi:10.1074/jbc.M802054200 Ossipov D, et al. Monoclonal antibody blockade of the human Eag1 potassium 26. Hayashi M, Kunii C, Takahata T, channel function exerts antitumor Ishikawa T. ATP-dependent regulation activity. Cancer Res 2007; 67:7343-9. of SK4/IK1-like currents in rat doi:10.1158/0008-5472.CAN-07-0107 submandibular acinar cells: possible

22. Gray AT, Zhao BB, Kindler CH, role of cAMP-dependent protein kinase. Winegar BD, Mazurek MJ, Xu J, et al. Am J Physiol Cell Physiol 2004; Volatile anesthetics activate the human 286:C635-46. tandem pore domain baseline K+ doi:10.1152/ajpcell.00283.2003 channel KCNK5. Anesthesiology 27. Hayashi M, Novak I. Molecular basis 2000; 92:1722-30. PMID:10839924 of potassium channels in pancreatic

23. Grissmer S, Dethlefs B, Wasmuth JJ, duct epithelial cells. Channels (Austin) Goldin AL, Gutman GA, Cahalan MD, 2013; 7:432-41.

Medical Research Archives, Vol. 4, Issue 4, August 2016 Potassium channels in pancreatic cancer

doi:10.4161/chan.26100 Adrenaline-induced hyperpolarization

28. Hayashi M, Wang J, Hede SE, Novak I. of mouse pancreatic islet cells is An intermediate-conductance mediated by G protein-gated inwardly Ca2+-activated K+ channel is important rectifying potassium (GIRK) channels. for secretion in pancreatic duct cells. Pflugers Arch 2008; 456:1097-108. Am J Physiol Cell Physiol 2012; doi:10.1007/s00424-008-0479-4 303:C151-9. 34. Jäger H, Dreker T, Buck A, Giehl K, doi:10.1152/ajpcell.00089.2012 Gress T, Grissmer S. Blockage of

29. Hede SE, Amstrup J, Klaerke DA, intermediate-conductance Ca2+-activated K+ channels inhibit Novak I. P2Y2 and P2Y4 receptors regulate pancreatic Ca2+-activated K+ human pancreatic cancer cell growth in channels differently. Pflugers Arch vitro. Mol Pharmacol 2004; 65:630-8. 2005; 450:429-36. doi:10.1124/mol.65.3.630 doi:10.1007/s00424-005-1433-3 35. Jensen BS, Strøbæk D, Christophersen

30. Hemmerlein B, Weseloh RM, Mello de P, Jørgensen TD, Hansen C, Queiroz F, Knötgen H, Sánchez A, Silahtaroglu A, et al. Characterization Rubio ME, et al. Overexpression of of the cloned human Eag1 potassium channels in clinical intermediate-conductance Ca2+-activated K+ channel. Am J tumours. Mol Cancer 2006; 5:41. doi:10.1186/1476-4598-5-41 Physiol 1998; 275:C848-56. PMID:9730970 31. Huang X, Jan LY. Targeting potassium channels in cancer. J Cell Biol 2014; 36. Jeong I, Choi BH, Yoon SH, Hahn SJ. 206:151-62. Carvedilol blocks the cloned cardiac doi:10.1083/jcb.201404136 Kv1.5 channels in a β-adrenergic receptor-independent manner. Biochem 32. Ishii TM, Silvia C, Hirschberg B, Bond Pharmacol 2012; 83:497-505. CT, Adelman JP, Maylie J. A human doi:10.1016/j.bcp.2011.11.019 intermediate conductance 37. Jin W, Lu Z. A novel high-affinity calcium-activated potassium channel. + Proc Natl Acad Sci U S A 1997; inhibitor for inward-rectifier K 94:11651-6. PMID:9326665 channels. Biochemistry 1998; 37:13291-9. doi:10.1021/bi981178p 33. Iwanir S, Reuveny E.

Medical Research Archives, Vol. 4, Issue 4, August 2016 Potassium channels in pancreatic cancer

38. Jin W, Lu Z. Synthesis of a stable form 43. Kobayashi T, Washiyama K, Ikeda K. of tertiapin: a high-affinity inhibitor for Inhibition of G protein-activated inward-rectifier K+ channels. inwardly rectifying K+ channels by Biochemistry 1999; 38:14286-93. fluoxetine (Prozac). Br J Pharmacol doi:10.1021/bi991205r 2003; 138:1119-28.

39. Joiner WJ, Wang LY, Tang MD, doi:10.1038/sj.bjp.0705172 Kaczmarek LK. hSK4, a member of a 44. Kobayashi T, Washiyama K, Ikeda K. novel subfamily of calcium-activated Inhibition of G protein-activated potassium channels. Proc Natl Acad inwardly rectifying K+ channels by Sci U S A 1997; 94:11013-8. various antidepressant drugs. PMID:9380751 Neuropsychopharmacology 2004;

40. Khanna R, Roy L, Zhu X, Schlichter 29:1841-51. LC. K+ channels and the microglial doi:10.1038/sj.npp.1300484 respiratory burst. Am J Physiol Cell 45. Kobayashi T, Washiyama K, Ikeda K. Physiol 2001; 280:C796-806. Inhibition of G protein-activated PMID:11245596 inwardly rectifying K+ channels by

41. Kindler CH, Paul M, Zou H, Liu C, different classes of antidepressants. Winegar BD, Gray AT, et al. Amide PLoS One 2011; 6:e28208. doi:10.1371/journal.pone.0028208 local anesthetics potently inhibit the human tandem pore domain 46. Krapivinsky G, Gordon EA, Wickman background K+ channel TASK-2 K, Velimirović B, Krapivinsky L, (KCNK5). J Pharmacol Exp Ther Clapham DE. The G-protein-gated + 2003; 306:84-92. atrial K channel IKACh is a doi:10.1124/jpet.103.049809 heteromultimer of two inwardly + 42. Kobayashi T, Ikeda K, Kumanishi T. rectifying K -channel proteins. Nature Inhibition by various antipsychotic 1995; 374:135-41. drugs of the G-protein-activated doi:10.1038/374135a0 inwardly rectifying K+ (GIRK) 47. Kubo Y, Reuveny E, Slesinger PA, Jan channels expressed in Xenopus oocytes. YN, Jan LY. Primary structure and Br J Pharmacol 2000; 129:1716-22. functional expression of a rat doi:10.1038/sj.bjp.0703224 G-protein-coupled muscarinic

Medical Research Archives, Vol. 4, Issue 4, August 2016 Potassium channels in pancreatic cancer

potassium channel. Nature 1993; Brüggemann A, Pardo LA, Marquardt 364:802-6. doi:10.1038/364802a0 A, et al. Functional expression of a rat

48. Kuras Z, Kucher V, Gordon SM, homologue of the voltage gated ether á Neumeier L, Chimote AA, Filipovich go-go potassium channel reveals differences in selectivity and activation AH, et al. Modulation of Kv1.3 channels by protein kinase A I in T kinetics between the Drosophila lymphocytes is mediated by the disc channel and its mammalian counterpart. large 1-tyrosine kinase Lck complex. EMBO J 1994; 13:4451-8. Am J Physiol Cell Physiol 2012; PMID:7925287 302:C1504-12. 53. Malayev AA, Nelson DJ, Philipson LH. doi:10.1152/ajpcell.00263.2011 Mechanism of clofilium block of the

49. La JH, Kang D, Park JY, Hong SG, human Kv1.5 delayed rectifier Han J. A novel acid-sensitive K+ potassium channel. Mol Pharmacol channel in rat dorsal root ganglia 1995; 47:198-205. PMID:7838129 neurons. Neurosci Lett 2006; 54. Matsubara H, Liman ER, Hess P, 406:244-9. Koren G. Pretranslational mechanisms doi:10.1016/j.neulet.2006.07.039 determine the type of potassium

50. Liao YJ, Jan YN, Jan LY. channels expressed in the rat skeletal and cardiac muscles. J Biol Chem Heteromultimerization of G-protein-gated inwardly rectifying K+ 1991; 266:13324-8. PMID:1712780 channel proteins GIRK1 and GIRK2 55. Morishige K, Inanobe A, Yoshimoto Y, and their altered expression in weaver Kurachi H, Murata Y, Tokunaga Y, et brain. J Neurosci 1996; 16:7137-50. al. Secretagogue-induced exocytosis PMID:8929423 recruits G protein-gated K+ channels to

51. Liu Y, Xu XH, Liu Z, Du XL, Chen plasma membrane in endocrine cells. J KH, Xin X, et al. Effects of the natural Biol Chem 1999; 274:7969-74. flavone trimethylapigenin on cardiac doi:10.1074/jbc.274.12.7969 potassium currents. Biochem 56. Morton MJ, Abohamed A, Pharmacol 2012; 84:498-506. Sivaprasadarao A, Hunter M. pH doi:10.1016/j.bcp.2012.05.002 sensing in the two-pore domain K+

52. Ludwig J, Terlau H, Wunder F, channel, TASK2. Proc Natl Acad Sci U

Medical Research Archives, Vol. 4, Issue 4, August 2016 Potassium channels in pancreatic cancer

S A 2005; 102:16102-6. 436:749-56. PMID:9716709

doi:10.1073/pnas.0506870102 62. Philipson LH, Hice RE, Schaefer K, 57. Niemeyer MI, Cid LP, Barros LF, LaMendola J, Bell GI, Nelson DJ, et al. Sepúlveda FV. Modulation of the Sequence and functional expression in two-pore domain acid-sensitive K+ Xenopus oocytes of a human channel TASK-2 (KCNK5) by changes insulinoma and islet potassium channel. in cell volume. J Biol Chem 2001; Proc Natl Acad Sci U S A 1991; 276:43166-74. 88:53-7. PMID:1986382

doi:10.1074/jbc.M107192200 63. Prevarskaya N, Skryma R, Shuba Y. 58. Occhiodoro T, Bernheim L, Liu JH, Ion channels and the hallmarks of Bijlenga P, Sinnreich M, Bader CR, et cancer. Trends Mol Med 2010; al. Cloning of a human ether-a-go-go 16:107-21. potassium channel expressed in doi:10.1016/j.molmed.2010.01.005

myoblasts at the onset of fusion. FEBS 64. Reuveny E, Slesinger PA, Inglese J, Lett 1998; 434:177-82. Morales JM, Iñiguez-Lluhi JA, doi:10.1016/S0014-5793(98)00973-9 Lefkowitz RJ, et al. Activation of the 59. Passadouro M, Faneca H. Managing cloned muscarinic potassium channel pancreatic adenocarcinoma: a special by G protein βγ subunits. Nature 1994; focus in microRNA gene therapy. Int J 370:143-6. doi:10.1038/370143a0

Mol Sci 2016; 17:718. 65. Reyes R, Duprat F, Lesage F, Fink M, doi:10.3390/ijms17050718 Salinas M, Farman N, et al. Cloning 60. Pedersen SF, Hoffmann EK, Novak I. and expression of a novel pH-sensitive Cell volume regulation in epithelial two pore domain K+ channel from physiology and cancer. Front Physiol human kidney. J Biol Chem 1998; 2013; 4:233. 273:30863-9. doi:10.3389/fphys.2013.00233 doi:10.1074/jbc.273.47.30863

61. Pellegrino M, Pellegrini M. 66. Schönherr R, Gessner G, Löber K, Modulation of Ca2+-activated K+ Heinemann SH. Functional distinction channels of human erythrocytes by of human EAG1 and EAG2 potassium endogenous cAMP-dependent protein channels. FEBS Lett 2002; 514:204-8. kinase. Pflugers Arch 1998; doi:10.1016/S0014-5793(02)02365-7

Medical Research Archives, Vol. 4, Issue 4, August 2016 Potassium channels in pancreatic cancer

67. Schönherr R, Löber K, Heinemann SH. transfected cell line. Proc Natl Acad Inhibition of human ether à go-go Sci U S A 1996; 93:9910-4. potassium channels by Ca2+/calmodulin. PMID:8790430

EMBO J 2000; 19:3263-71. 72. Steward MC, Ishiguro H, Case RM. doi:10.1093/emboj/19.13.3263 Mechanisms of bicarbonate secretion 68. Singh S, Syme CA, Singh AK, Devor in the pancreatic duct. Annu Rev DC, Bridges RJ. Benzimidazolone Physiol 2005; 67:377-409. activators of chloride secretion: doi:10.1146/annurev.physiol.67.03110 potential therapeutics for cystic fibrosis 3.153247 and chronic obstructive pulmonary 73. Strutz-Seebohm N, Gutcher I, Decher disease. J Pharmacol Exp Ther 2001; N, Steinmeyer K, Lang F, Seebohm G. 296:600-11. PMID:11160649 Comparison of potent Kv1.5 potassium 69. Snyders DJ, Knoth KM, Roberds SL, channel inhibitors reveals the Tamkun MM. Time-, voltage-, and molecular basis for blocking kinetics state-dependent block by quinidine of a and binding mode. Cell Physiol cloned human cardiac potassium Biochem 2007; 20:791-800. channel. Mol Pharmacol 1992; doi:10.1159/000110439

41:322-30. PMID:1538710 74. Stühmer W, Ruppersberg JP, Schröter 70. Snyders DJ, Tamkun MM, Bennett PB. KH, Sakmann B, Stocker M, Giese KP, A rapidly activating and slowly et al. Molecular basis of functional inactivating potassium channel cloned diversity of voltage-gated potassium from human heart. Functional analysis channels in mammalian brain. EMBO J after stable mammalian cell culture 1989; 8:3235-44. PMID:2555158

expression. J Gen Physiol 1993; 75. Swanson R, Marshall J, Smith JS, 101:513-43. PMID:8505626 Williams JB, Boyle MB, Folander K, et 71. Stansfeld CE, Röper J, Ludwig J, al. Cloning and expression of cDNA Weseloh RM, Marsh SJ, Brown DA, et and genomic clones encoding three al. Elevation of intracellular calcium by delayed rectifier potassium channels in muscarinic receptor activation induces rat brain. Neuron 1990; 4:929-39. a block of voltage-activated rat doi:10.1016/0896-6273(90)90146-7

ether-à-go-go channels in a stably 76. von Hahn T, Thiele I, Zingaro L,

Medical Research Archives, Vol. 4, Issue 4, August 2016 Potassium channels in pancreatic cancer

Hamm K, Garcia-Alzamora M, channel-deficient mice reveals a Köttgen M, et al. Characterisation of mechanism for stabilizing bicarbonate the rat SK4/IK1 K+ channel. Cell transport. Proc Natl Acad Sci U S A Physiol Biochem 2001; 11:219-30. 2004; 101:8215-20. doi:10.1159/000051936 doi:10.1073/pnas.0400081101

77. Wang J, Haanes KA, Novak I. 81. Wulf A, Schwab A. Regulation of a Purinergic regulation of CFTR and calcium-sensitive K+ channel (cIK1) by Ca2+-activated Cl− channels and K+ protein kinase C. J Membr Biol 2002; channels in human pancreatic duct 187:71-9. epithelium. Am J Physiol Cell Physiol doi:10.1007/s00232-001-0149-3

2013; 304:C673-84. 82. Wulff H, Miller MJ, Hänsel W, doi:10.1152/ajpcell.00196.2012 Grissmer S, Cahalan MD, Chandy KG. 78. Wang S, Benamer N, Zanella S, Kumar Design of a potent and selective NN, Shi Y, Bévengut M, et al. TASK-2 inhibitor of the channels contribute to pH sensitivity of intermediate-conductance retrotrapezoid nucleus chemoreceptor Ca2+-activated K+ channel, IKCa1: a neurons. J Neurosci 2013; 33:16033-44. potential immunosuppressant. Proc doi:10.1523/JNEUROSCI.2451-13.201 Natl Acad Sci U S A 2000; 97:8151-6. 3 doi:10.1073/pnas.97.14.8151

79. Warmke JW, Ganetzky B. A family of 83. Ye F, Hu Y, Yu W, Xie Z, Hu J, Cao Z, potassium channel genes related to eag et al. The scorpion toxin analogue in Drosophila and mammals. Proc Natl BmKTX-D33H as a potential Kv1.3 Acad Sci U S A 1994; 91:3438-42. channel-selective immunomodulator PMID:8159766 for autoimmune diseases. Toxins

80. Warth R, Barrière H, Meneton P, Bloch (Basel) 2016; 8:115 M, Thomas J, Tauc M, et al. Proximal doi:10.3390/toxins8040115 renal tubular acidosis in TASK2 K+