Home Life Sciences Pancreatic KCa3.1 channels in health and disease
Article
Licensed
Unlicensed Requires Authentication

Pancreatic KCa3.1 channels in health and disease

  • Benjamin Soret , Jurek Hense , Simon Lüdtke , Insa Thale , Albrecht Schwab and Martina Düfer ORCID logo EMAIL logo
Published/Copyright: December 27, 2022
Biological Chemistry
From the journal Biological Chemistry Volume 404 Issue 4

Abstract

Ion channels play an important role for regulation of the exocrine and the endocrine pancreas. This review focuses on the Ca2+-regulated K+ channel KCa3.1, encoded by the KCNN4 gene, which is present in both parts of the pancreas. In the islets of Langerhans, KCa3.1 channels are involved in the regulation of membrane potential oscillations characterizing nutrient-stimulated islet activity. Channel upregulation is induced by gluco- or lipotoxic conditions and might contribute to micro-inflammation and impaired insulin release in type 2 diabetes mellitus as well as to diabetes-associated renal and vascular complications. In the exocrine pancreas KCa3.1 channels are expressed in acinar and ductal cells. They are thought to play a role for anion secretion during digestion but their physiological role has not been fully elucidated yet. Pancreatic carcinoma, especially pancreatic ductal adenocarcinoma (PDAC), is associated with drastic overexpression of KCa3.1. For pharmacological targeting of KCa3.1 channels, we are discussing the possible benefits KCa3.1 channel inhibitors might provide in the context of diabetes mellitus and pancreatic cancer, respectively. We are also giving a perspective for the use of a fluorescently labeled derivative of the KCa3.1 blocker senicapoc as a tool to monitor channel distribution in pancreatic tissue. In summary, modulating KCa3.1 channel activity is a useful strategy for exo-and endocrine pancreatic disease but further studies are needed to evaluate its clinical suitability.

Keywords: diabetes; islet of Langerhans; KCa3.1; KCNN4 ; pancreatic cancer; PDAC
Corresponding author: Martina Düfer, University of Münster, Institute of Pharmaceutical and Medicinal Chemistry, Department of Pharmacology, Corrensstraße 48, D-48149 Münster, Germany, E-mail:
Benjamin Soret and Jurek Hense contributed equally to this work.

Funding source: Deutsche Forschungsgemeinschaft

Award Identifier / Grant number: GRK 2515

Award Identifier / Grant number: SCHW 407/22-1

Award Identifier / Grant number: SCHW 407/25-1

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This work was supported by the Deutsche Forschungsgemeinschaft (Research Training Group GRK 2515, Chemical Biology of Ion Channels). A.S. acknowledges the support by the Deutsche Forschungsgemeinschaft (SCHW 407/22-1 and SCHW 407/25-1).

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

References

Andersen, D.K., Korc, M., Petersen, G.M., Eibl, G., Li, D., Rickels, M.R., Chari, S.T., and Abbruzzese, J.L. (2017). Diabetes, pancreatogenic diabetes, and pancreatic cancer. Diabetes 66: 1103–1110, https://doi.org/10.2337/db16-1477.Search in Google Scholar PubMed PubMed Central

Apte, M.V., Pirola, R.C., and Wilson, J.S. (2012). Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front. Physiol. 3: 344, https://doi.org/10.3389/fphys.2012.00344.Search in Google Scholar PubMed PubMed Central

Arnush, M., Heitmeier, M.R., Scarim, A.L., Marino, M.H., Manning, P.T., and Corbett, J.A. (1998). IL-1 produced and released endogenously within human islets inhibits beta cell function. J. Clin. Invest. 102: 516–526, https://doi.org/10.1172/jci844.Search in Google Scholar

Ataga, K.I., Smith, W.R., Castro, L.M.de, Swerdlow, P., Saunthararajah, Y., Castro, O., Vichinsky, E., Kutlar, A., Orringer, E.P., Rigdon, G.C., et al.. (2008). Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. Blood 111: 3991–3997, https://doi.org/10.1182/blood-2007-08-110098.Search in Google Scholar PubMed

Backx, E., Coolens, K., van den Bossche, J.L., Houbracken, I., Espinet, E., and Rooman, I. (2022). On the origin of pancreatic cancer: molecular tumor subtypes in perspective of exocrine cell plasticity. Cell. Mol. Gastroenterol. Hepatol. 13: 1243–1253, https://doi.org/10.1016/j.jcmgh.2021.11.010.Search in Google Scholar PubMed PubMed Central

Blaszczak, W. and Swietach, P. (2021). What do cellular responses to acidity tell us about cancer? Cancer Metastasis Rev. 40: 1159–1176, https://doi.org/10.1007/s10555-021-10005-3.Search in Google Scholar PubMed PubMed Central

Böni-Schnetzler, M., Thorne, J., Parnaud, G., Marselli, L., Ehses, J.A., Kerr-Conte, J., Pattou, F., Halban, P.A., Weir, G.C., and Donath, M.Y. (2008). Increased interleukin (IL)-1beta messenger ribonucleic acid expression in beta -cells of individuals with type 2 diabetes and regulation of IL-1beta in human islets by glucose and autostimulation. J. Clin. Endocrinol. Metab. 93: 4065–4074, https://doi.org/10.1210/jc.2008-0396.Search in Google Scholar PubMed PubMed Central

Bonito, B., Sauter, D.R.P., Schwab, A., Djamgoz, M.B.A., and Novak, I. (2016). KCa3.1 (IK) modulates pancreatic cancer cell migration, invasion and proliferation: anomalous effects on TRAM-34. Pflugers. Arch. 468: 1865–1875, https://doi.org/10.1007/s00424-016-1891-9.Search in Google Scholar PubMed

Brömmel, K., Maskri, S., Maisuls, I., Konken, C.P., Rieke, M., Pethő, Z., Strassert, C.A., Koch, O., Schwab, A., and Wünsch, B. (2020). Synthesis of small-molecule fluorescent probes for the in vitro imaging of calcium-activated potassium channel KCa 3.1. Angew Chem. Int. Ed. Engl. 59: 8277–8284, https://doi.org/10.1002/ange.202001201.Search in Google Scholar

Brown, B.M., Pressley, B., and Wulff, H. (2018). KCa3.1 channel modulators as potential therapeutic compounds for glioblastoma. Curr. Neuropharmacol. 16: 618–626, https://doi.org/10.2174/1570159x15666170630164226.Search in Google Scholar

Bulk, E., Todesca, L.M., Bachmann, M., Szabo, I., Rieke, M., and Schwab, A. (2022). Functional expression of mitochondrial KCa3.1 channels in non-small cell lung cancer cells. Pflügers. Arch. 474: 1147–1157, https://doi.org/10.1007/s00424-022-02748-x.Search in Google Scholar PubMed PubMed Central

Burke, S.J., Karlstad, M.D., Regal, K.M., Sparer, T.E., Lu, D., Elks, C.M., Grant, R.W., Stephens, J.M., Burk, D.H., and Collier, J.J. (2015). CCL20 is elevated during obesity and differentially regulated by NF-κB subunits in pancreatic β-cells. Biochim. Biophys. Acta 1849: 637–652, https://doi.org/10.1016/j.bbagrm.2015.03.007.Search in Google Scholar PubMed PubMed Central

Chimote, A.A., Balajthy, A., Arnold, M.J., Newton, H.S., Hajdu, P., Qualtieri, J., Wise-Draper, T., and Conforti, L. (2018). A defect in KCa3.1 channel activity limits the ability of CD8+ T cells from cancer patients to infiltrate an adenosine-rich microenvironment. Sci. Signal. 11: eaaq1616, https://doi.org/10.1126/scisignal.aaq1616.Search in Google Scholar PubMed PubMed Central

Chung, K.M., Singh, J., Lawres, L., Dorans, K.J., Garcia, C., Burkhardt, D.B., Robbins, R., Bhutkar, A., Cardone, R., Zhao, X., et al.. (2020). Endocrine-exocrine signaling drives obesity-associated pancreatic ductal adenocarcinoma. Cell 181: 832–847.e18, https://doi.org/10.1016/j.cell.2020.03.062.Search in Google Scholar PubMed PubMed Central

Coderre, L., Debieche, L., Plourde, J., Rabasa-Lhoret, R., and Lesage, S. (2021). The potential causes of cystic fibrosis-related diabetes. Front. Endocrinol. 12: 702823, https://doi.org/10.3389/fendo.2021.702823.Search in Google Scholar PubMed PubMed Central

Drews, G., Krippeit-Drews, P., and Düfer, M. (2015). Electrophysiology of islet cells. In: Islam, M.S. (Ed.), Islets of Langerhans. Springer, Dordrecht, pp. 249–303.10.1007/978-94-007-6686-0_5Search in Google Scholar

Düfer, M., Gier, B., Wolpers, D., Krippeit-Drews, P., Ruth, P., and Drews, G. (2009). Enhanced glucose tolerance by SK4 channel inhibition in pancreatic beta-cells. Diabetes 58: 1835–1843, https://doi.org/10.2337/db08-1324.Search in Google Scholar PubMed PubMed Central

Eichler, I., Wibawa, J., Grgic, I., Knorr, A., Brakemeier, S., Pries, A.R., Hoyer, J., and Köhler, R. (2003). Selective blockade of endothelial Ca2+-activated small- and intermediate-conductance K+-channels suppresses EDHF-mediated vasodilation. Br. J. Pharmacol. 138: 594–601, https://doi.org/10.1038/sj.bjp.0705075.Search in Google Scholar PubMed PubMed Central

Eil, R., Vodnala, S.K., Clever, D., Klebanoff, C.A., Sukumar, M., Pan, J.H., Palmer, D.C., Gros, A., Yamamoto, T.N., Patel, S.J., et al.. (2016). Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537: 539–543, https://doi.org/10.1038/nature19364.Search in Google Scholar PubMed PubMed Central

Estes, D.J., Memarsadeghi, S., Lundy, S.K., Marti, F., Mikol, D.D., Fox, D.A., and Mayer, M. (2008). High-throughput profiling of ion channel activity in primary human lymphocytes. Anal. Chem. 80: 3728–3735, https://doi.org/10.1021/ac800164v.Search in Google Scholar PubMed

Fanger, C.M., Ghanshani, S., Logsdon, N.J., Rauer, H., Kalman, K., Zhou, J., Beckingham, K., Chandy, K.G., Cahalan, M.D., and Aiyar, J. (1999). Calmodulin mediates calcium-dependent activation of the intermediate conductance KCa channel IKCa1. J. Biol. Chem. 274: 5746–5754, https://doi.org/10.1074/jbc.274.9.5746.Search in Google Scholar PubMed

Garg, B., Giri, B., Modi, S., Sethi, V., Castro, I., Umland, O., Ban, Y., Lavania, S., Dawra, R., Banerjee, S., et al.. (2018). NF-κB in pancreatic stellate cells reduces infiltration of tumors by cytotoxic T cells and killing of cancer cells, via up-regulation of CXCL12. Gastroenterology 155: 880–891.e8, https://doi.org/10.1053/j.gastro.2018.05.051.Search in Google Scholar PubMed PubMed Central

Gerlach, A.C., Gangopadhyay, N.N., and Devor, D.C. (2000). Kinase-dependent regulation of the intermediate conductance, calcium-dependent potassium channel hIK1. J. Biol. Chem. 275: 585–598, https://doi.org/10.1074/jbc.275.1.585.Search in Google Scholar PubMed

Ghanshani, S., Wulff, H., Miller, M.J., Rohm, H., Neben, A., Gutman, G.A., Cahalan, M.D., and Chandy, K.G. (2000). Up-regulation of the IKCa1 potassium channel during T-cell activation. Molecular mechanism and functional consequences. J. Biol. Chem. 275: 37137–37149, https://doi.org/10.1074/jbc.m003941200.Search in Google Scholar

Glaser, F., Hundehege, P., Bulk, E., Todesca, L.M., Schimmelpfennig, S., Nass, E., Budde, T., Meuth, S.G., and Schwab, A. (2021). KCa channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549). Sci. Rep. 11: 18330, https://doi.org/10.1038/s41598-021-97406-0.Search in Google Scholar PubMed PubMed Central

Glaser, N., Little, C., Lo, W., Cohen, M., Tancredi, D., Wulff, H., and O’Donnell, M. (2017). Treatment with the KCa3.1 inhibitor TRAM-34 during diabetic ketoacidosis reduces inflammatory changes in the brain. Pediatr. Diabetes 18: 356–366, https://doi.org/10.1111/pedi.12396.Search in Google Scholar PubMed

Grgic, I., Eichler, I., Heinau, P., Si, H., Brakemeier, S., Hoyer, J., and Köhler, R. (2005). Selective blockade of the intermediate-conductance Ca2+-activated K+ channel suppresses proliferation of microvascular and macrovascular endothelial cells and angiogenesis in vivo. Arterioscler. Thromb. Vasc. Biol. 25: 704–709, https://doi.org/10.1161/01.atv.0000156399.12787.5c.Search in Google Scholar

Grgic, I., Kiss, E., Kaistha, B.P., Busch, C., Kloss, M., Sautter, J., Müller, A., Kaistha, A., Schmidt, C., Raman, G., et al.. (2009). Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels. Proc. Natl. Acad. Sci. USA 106: 14518–14523, https://doi.org/10.1073/pnas.0903458106.Search in Google Scholar PubMed PubMed Central

Hayashi, M. and Novak, I. (2013). Molecular basis of potassium channels in pancreatic duct epithelial cells. Channels 7: 432–441, https://doi.org/10.4161/chan.26100.Search in Google Scholar PubMed PubMed Central

Hayashi, M., Wang, J., Hede, S.E., and Novak, I. (2012). An intermediate-conductance Ca2+-activated K+ channel is important for secretion in pancreatic duct cells. Am. J. Physiol. Cell Physiol. 303: C151–C159, https://doi.org/10.1152/ajpcell.00089.2012.Search in Google Scholar PubMed

Henley, S.J., Ward, E.M., Scott, S., Ma, J., Anderson, R.N., Firth, A.U., Thomas, C.C., Islami, F., Weir, H.K., Lewis, D.R., et al.. (2020). Annual report to the nation on the status of cancer, part I: national cancer statistics. Cancer 126: 2225–2249, https://doi.org/10.1002/cncr.32802.Search in Google Scholar PubMed PubMed Central

Henquin, J.C., Dufrane, D., Gmyr, V., Kerr-Conte, J., and Nenquin, M. (2017). Pharmacological approach to understanding the control of insulin secretion in human islets. Diabetes Obes. Metabol. 19: 1061–1070, https://doi.org/10.1111/dom.12887.Search in Google Scholar PubMed

Henríquez, C., Riquelme, T.T., Vera, D., Julio-Kalajzić, F., Ehrenfeld, P., Melvin, J.E., Figueroa, C.D., Sarmiento, J., and Flores, C.A. (2016). The calcium-activated potassium channel KCa3.1 plays a central role in the chemotactic response of mammalian neutrophils. Acta Physiol. 216: 132–145, https://doi.org/10.1111/apha.12548.Search in Google Scholar PubMed PubMed Central

Henze, L.A., Estepa, M., Pieske, B., Lang, F., Eckardt, K.-U., Alesutan, I., and Voelkl, J. (2021). Zinc ameliorates the osteogenic effects of high glucose in vascular smooth muscle cells. Cells 10: 3083, https://doi.org/10.3390/cells10113083.Search in Google Scholar PubMed PubMed Central

Hiraoka, N., Ino, Y., Sekine, S., Tsuda, H., Shimada, K., Kosuge, T., Zavada, J., Yoshida, M., Yamada, K., Koyama, T., et al.. (2010). Tumour necrosis is a postoperative prognostic marker for pancreatic cancer patients with a high interobserver reproducibility in histological evaluation. Br. J. Cancer 103: 1057–1065, https://doi.org/10.1038/sj.bjc.6605854.Search in Google Scholar PubMed PubMed Central

Hofschröer, V., Najder, K., Rugi, M., Bouazzi, R., Cozzolino, M., Arcangeli, A., Panyi, G., and Schwab, A. (2020). Ion channels orchestrate pancreatic ductal adenocarcinoma progression and therapy. Front. Pharmacol. 11: 586599, https://doi.org/10.3389/fphar.2020.586599.Search in Google Scholar PubMed PubMed Central

Hosein, A.N., Brekken, R.A., and Maitra, A. (2020). Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat. Rev. Gastroenterol. Hepatol. 17: 487–505, https://doi.org/10.1038/s41575-020-0300-1.Search in Google Scholar PubMed PubMed Central

Huang, C., Chen, X.M., and Pollock, C.A. (2022). KCa3.1 in diabetic kidney disease. Curr. Opin. Nephrol. Hypertens. 31: 129–134, https://doi.org/10.1097/mnh.0000000000000751.Search in Google Scholar

Huang, C., Lin, M.Z., Cheng, D., Braet, F., Pollock, C.A., and Chen, X.M. (2016). KCa3.1 mediates dysfunction of tubular autophagy in diabetic kidneys via PI3k/Akt/mTOR signaling pathways. Sci. Rep. 6: 23884, https://doi.org/10.1038/srep23884.Search in Google Scholar PubMed PubMed Central

Huang, C., Pollock, C.A., and Chen, X.M. (2014a). High glucose induces CCL20 in proximal tubular cells via activation of the KCa3.1 channel. PLoS One 9: e95173, https://doi.org/10.1371/journal.pone.0095173.Search in Google Scholar PubMed PubMed Central

Huang, C., Shen, S., Ma, Q., Chen, J., Gill, A., Pollock, C.A., and Chen, X.M. (2013). Blockade of KCa3.1 ameliorates renal fibrosis through the TGF-β1/Smad pathway in diabetic mice. Diabetes 62: 2923–2934, https://doi.org/10.2337/db13-0135.Search in Google Scholar PubMed PubMed Central

Huang, C., Shen, S., Ma, Q., Gill, A., Pollock, C.A., and Chen, X.M. (2014b). KCa3.1 mediates activation of fibroblasts in diabetic renal interstitial fibrosis. Nephrol. Dial. Transplant. 29: 313–324, https://doi.org/10.1093/ndt/gft431.Search in Google Scholar PubMed PubMed Central

Igoillo-Esteve, M., Marselli, L., Cunha, D.A., Ladrière, L., Ortis, F., Grieco, F.A., Dotta, F., Weir, G.C., Marchetti, P., Eizirik, D.L., et al.. (2010). Palmitate induces a pro-inflammatory response in human pancreatic islets that mimics CCL2 expression by beta cells in type 2 diabetes. Diabetologia 53: 1395–1405, https://doi.org/10.1007/s00125-010-1707-y.Search in Google Scholar PubMed

Ishii, T.M., Silvia, C., Hirschberg, B., Bond, C.T., Adelman, J.P., and Maylie, J. (1997). A human intermediate conductance calcium-activated potassium channel. Proc. Natl. Acad. Sci. USA 94: 11651–11656, https://doi.org/10.1073/pnas.94.21.11651.Search in Google Scholar PubMed PubMed Central

Jäger, H., Dreker, T., Buck, A., Giehl, K., Gress, T., and Grissmer, S. (2004). Blockage of intermediate-conductance Ca2+-activated K+ channels inhibit human pancreatic cancer cell growth in vitro. Mol. Pharmacol. 65: 630–638, https://doi.org/10.1124/mol.65.3.630.Search in Google Scholar PubMed

Jiang, S., Zhu, L., Yang, J., Hu, L., Gu, J., Xing, X., Sun, Y., and Zhang, Z. (2017). Integrated expression profiling of potassium channels identifys KCNN4 as a prognostic biomarker of pancreatic cancer. Biochem. Biophys. Res. Commun. 494: 113–119, https://doi.org/10.1016/j.bbrc.2017.10.072.Search in Google Scholar PubMed

Jiang, S.H., Zhu, L.L., Zhang, M., Li, R.K., Yang, Q., Yan, J.Y., Zhang, C., Yang, J.Y., Dong, F.Y., Dai, M., et al.. (2019). GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca2+ signalling in a GABA-independent manner. Gut 68: 1994–2006, https://doi.org/10.1136/gutjnl-2018-317479.Search in Google Scholar PubMed

Jin, G., Hong, W., Guo, Y., Bai, Y., and Chen, B. (2020). Molecular mechanism of pancreatic stellate cells activation in chronic pancreatitis and pancreatic cancer. J. Cancer 11: 1505–1515, https://doi.org/10.7150/jca.38616.Search in Google Scholar PubMed PubMed Central

Jin, L.W., Lucente, J.D., Nguyen, H.M., Singh, V., Singh, L., Chavez, M., Bushong, T., Wulff, H., and Maezawa, I. (2019). Repurposing the KCa3.1 inhibitor senicapoc for Alzheimer’s disease. Ann. Clin. Transl. Neurol. 6: 723–738, https://doi.org/10.1002/acn3.754.Search in Google Scholar PubMed PubMed Central

Jung, S.R., Kim, K., Hille, B., Nguyen, T.D., and Koh, D.S. (2006). Pattern of Ca2+ increase determines the type of secretory mechanism activated in dog pancreatic duct epithelial cells. J. Physiol. 576: 163–178, https://doi.org/10.1113/jphysiol.2006.114876.Search in Google Scholar PubMed PubMed Central

Kacar, A.K. (2020). Indomethacin decreases insulin secretion by reducing KCa3.1 as a biomarker of pancreatic tumor and causes apoptotic cell death. J. Biochem. Mol. Toxicol. 34: e22488, https://doi.org/10.1002/jbt.22488.Search in Google Scholar

Kleeff, J., Kusama, T., Rossi, D.L., Ishiwata, T., Maruyama, H., Friess, H., Büchler, M.W., Zlotnik, A., and Korc, M. (1999). Detection and localization of Mip-3α/LARC/Exodus, a macrophage proinflammatory chemokine, and its CCR6 receptor in human pancreatic cancer. Int. J. Cancer 81: 650–657, https://doi.org/10.1002/(sici)1097-0215(19990517)81:4<650::aid-ijc23>3.0.co;2-#.10.1002/(SICI)1097-0215(19990517)81:4<650::AID-IJC23>3.0.CO;2-#Search in Google Scholar

Köhler, R., Degenhardt, C., Kühn, M., Runkel, N., Paul, M., and Hoyer, J. (2000). Expression and function of endothelial Ca2+-activated K+ channels in human mesenteric artery: a single-cell reverse transcriptase-polymerase chain reaction and electrophysiological study in situ. Circ. Res. 87: 496–503, https://doi.org/10.1161/01.res.87.6.496.Search in Google Scholar

Koshy, S., Wu, D., Hu, X., Tajhya, R.B., Huq, R., Khan, F.S., Pennington, M.W., Wulff, H., Yotnda, P., and Beeton, C. (2013). Blocking KCa3.1 channels increases tumor cell killing by a subpopulation of human natural killer lymphocytes. PLoS One 8: e76740, https://doi.org/10.1371/journal.pone.0076740.Search in Google Scholar

Kovalenko, I., Glasauer, A., Schöckel, L., Sauter, D.R.P., Ehrmann, A., Sohler, F., Hägebarth, A., Novak, I., and Christian, S. (2016). Identification of KCa3.1 channel as a novel regulator of oxidative phosphorylation in a subset of pancreatic carcinoma cell lines. PLoS One 11: e0160658, https://doi.org/10.1371/journal.pone.0160658.Search in Google Scholar

Kuntze, A., Goetsch, O., Fels, B., Najder, K., Unger, A., Wilhelmi, M., Sargin, S., Schimmelpfennig, S., Neumann, I., Schwab, A., et al.. (2020). Protonation of Piezo1 impairs cell-matrix interactions of pancreatic stellate cells. Front. Physiol. 11: 89, https://doi.org/10.3389/fphys.2020.00089.Search in Google Scholar

Li, X., Liu, Y., Cao, A., Li, C., Wang, L., Wu, Q., Li, X., Lv, X., Zhu, J., Chun, H., et al.. (2021). Crocin improves endothelial mitochondrial dysfunction via GPx1/ROS/KCa3.1 signal axis in diabetes. Front. Cell Dev. Biol. 9: 651434, https://doi.org/10.3389/fcell.2021.651434.Search in Google Scholar

Maedler, K., Sergeev, P., Ris, F., Oberholzer, J., Joller-Jemelka, H.I., Spinas, G.A., Kaiser, N., Halban, P.A., and Donath, M.Y. (2002). Glucose-induced beta cell production of IL-1β contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest. 110: 851–860, https://doi.org/10.1172/jci200215318.Search in Google Scholar

Mato, E., Lucas, M., Petriz, J., Gomis, R., and Novials, A. (2009). Identification of a pancreatic stellate cell population with properties of progenitor cells: new role for stellate cells in the pancreas. Biochem. J. 421: 181–191, https://doi.org/10.1042/bj20081466.Search in Google Scholar

Maylie, J., Bond, C.T., Herson, P.S., Lee, W.S., and Adelman, J.P. (2004). Small conductance Ca2+-activated K+ channels and calmodulin. J. Physiol. 554: 255–261, https://doi.org/10.1113/jphysiol.2003.049072.Search in Google Scholar

McFerrin, M.B., Turner, K.L., Cuddapah, V.A., and Sontheimer, H. (2012). Differential role of IK and BK potassium channels as mediators of intrinsic and extrinsic apoptotic cell death. Am. J. Physiol. Cell Physiol. 303: C1070–C1078, https://doi.org/10.1152/ajpcell.00040.2012.Search in Google Scholar PubMed PubMed Central

Mishra, R.C., Kyle, B.D., Kendrick, D.J., Svystonyuk, D., Kieser, T.M., Fedak, P.W.M., Wulff, H., and Braun, A.P. (2021). KCa channel activation normalizes endothelial function in Type 2 Diabetic resistance arteries by improving intracellular Ca2+ mobilization. Metabolism 114: 154390, https://doi.org/10.1016/j.metabol.2020.154390.Search in Google Scholar PubMed PubMed Central

Mo, X., Zhang, C.F., Xu, P., Ding, M., Ma, Z.J., Sun, Q., Liu, Y., Bi, H.K., Guo, X., Abdelatty, A., et al.. (2022). KCNN4-mediated Ca2+/MET/AKT axis is promising for targeted therapy of pancreatic ductal adenocarcinoma. Acta Pharmacol. Sin. 43: 735–746, https://doi.org/10.1038/s41401-021-00688-3.Search in Google Scholar PubMed PubMed Central

Mohr, C.J., Gross, D., Sezgin, E.C., Steudel, F.A., Ruth, P., Huber, S.M., and Lukowski, R. (2019a). KCa3.1 channels confer radioresistance to breast cancer cells. Cancers 11: 128, https://doi.org/10.3390/cancers11091285.Search in Google Scholar PubMed PubMed Central

Mohr, C.J., Steudel, F.A., Gross, D., Ruth, P., Lo, W.Y., Hoppe, R., Schroth, W., Brauch, H., Huber, S.M., and Lukowski, R. (2019b). Cancer-associated intermediate conductance Ca2+-activated K⁺ channel KCa3. Cancers 111: 109, https://doi.org/10.3390/cancers11010109.Search in Google Scholar PubMed PubMed Central

Møller, L.S., Fialla, A.D., Schierwagen, R., Biagini, M., Liedtke, C., Laleman, W., Klein, S., Reul, W., Koch Hansen, L., Rabjerg, M., et al.. (2016). The calcium-activated potassium channel KCa3.1 is an important modulator of hepatic injury. Sci. Rep. 6: 28770, https://doi.org/10.1038/srep28770.Search in Google Scholar PubMed PubMed Central

Nguyen, H.M., Singh, V., Pressly, B., Jenkins, D.P., Wulff, H., and Yarov-Yarovoy, V. (2017). Structural insights into the atomistic mechanisms of action of small molecule inhibitors targeting the KCa3.1 channel pore. Mol. Pharmacol. 91: 392–402, https://doi.org/10.1124/mol.116.108068.Search in Google Scholar PubMed PubMed Central

Nguyen, T.D. and Moody, M.W. (1998). Calcium-activated potassium conductances on cultured nontransformed dog pancreatic duct epithelial cells. Pancreas 17: 348–358, https://doi.org/10.1097/00006676-199811000-00005.Search in Google Scholar PubMed

Paka, L., Smith, D.E., Jung, D., McCormack, S., Zhou, P., Duan, B., Li, J.S., Shi, J., Hao, Y.J., Jiang, K., et al.. (2017). Anti-steatotic and anti-fibrotic effects of the KCa3.1 channel inhibitor, Senicapoc, in non-alcoholic liver disease. World J. Gastroenterol. 23: 4181–4190, https://doi.org/10.3748/wjg.v23.i23.4181.Search in Google Scholar PubMed PubMed Central

Pang, Z.D., Wang, Y., Wang, X.J., She, G., Ma, X.Z., Song, Z., Zhao, L.M., Wang, H.F., Lai, B.C., Gou, W., et al.. (2019). KCa3.1 channel mediates inflammatory signaling of pancreatic β cells and progression of type 2 diabetes mellitus. Faseb. J. 33: 14760–14771, https://doi.org/10.1096/fj.201901329rr.Search in Google Scholar PubMed

Park, W., Chawla, A., and O’Reilly, E.M. (2021). Pancreatic cancer: a review. J. Am. Med. Assoc. 326: 851–862, https://doi.org/10.1001/jama.2021.13027.Search in Google Scholar PubMed PubMed Central

Pedersen, K.A., Jørgensen, N.K., Jensen, B.S., and Olesen, S.P. (2000). Inhibition of the human intermediate-conductance, Ca2+-activated K+ channel by intracellular acidification. Pflügers Arch. 440: 153–156, https://doi.org/10.1007/s004240000269.Search in Google Scholar PubMed

Pedersen, S.F., Novak, I., Alves, F., Schwab, A., and Pardo, L.A. (2017). Alternating pH landscapes shape epithelial cancer initiation and progression: focus on pancreatic cancer. Bioessays 39: 1600253, https://doi.org/10.1002/bies.201600253.Search in Google Scholar PubMed

Pethő, Z., Najder, K., Bulk, E., and Schwab, A. (2019). Mechanosensitive ion channels push cancer progression. Cell Calcium 80: 79–90, https://doi.org/10.1016/j.ceca.2019.03.007.Search in Google Scholar PubMed

Pethő, Z., Najder, K., Carvalho, T., McMorrow, R., Todesca, L.M., Rugi, M., Bulk, E., Chan, A., Löwik, C.W.G.M., Reshkin, S.J., et al.. (2020). pH-channeling in cancer: how pH-dependence of cation channels shapes cancer pathophysiology. Cancers 12: 2484, https://doi.org/10.3390/cancers12092484.Search in Google Scholar PubMed PubMed Central

Phillips, P.A., Yang, L., Shulkes, A., Vonlaufen, A., Poljak, A., Bustamante, S., Warren, A., Xu, Z., Guilhaus, M., Pirola, R., et al.. (2010). Pancreatic stellate cells produce acetylcholine and may play a role in pancreatic exocrine secretion. Proc. Natl. Acad. Sci. USA 107: 17397–17402, https://doi.org/10.1073/pnas.1000359107.Search in Google Scholar PubMed PubMed Central

Pinilla, E., Sánchez, A., Martínez, M.P., Muñoz, M., García-Sacristán, A., Köhler, R., Prieto, D., and Rivera, L. (2021). Endothelial KCa 1.1 and KCa 3.1 channels mediate rat intrarenal artery endothelium-derived hyperpolarization response. Acta Physiol. 231: e13598, https://doi.org/10.1111/apha.13598.Search in Google Scholar PubMed

Prevarskaya, N., Skryma, R., and Shuba, Y. (2018). Ion channels in cancer: are cancer hallmarks oncochannelopathies? Physiol. Rev. 98: 559–621, https://doi.org/10.1152/physrev.00044.2016.Search in Google Scholar PubMed

Provenzano, P.P., Cuevas, C., Chang, A.E., Goel, V.K., Hoff, D.D.von, and Hingorani, S.R. (2012). Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21: 418–429, https://doi.org/10.1016/j.ccr.2012.01.007.Search in Google Scholar PubMed PubMed Central

Rabjerg, M., Oliván-Viguera, A., Hansen, L.K., Jensen, L., Sevelsted-Møller, L., Walter, S., Jensen, B.L., Marcussen, N., and Köhler, R. (2015). High expression of KCa3.1 in patients with clear cell renal carcinoma predicts high metastatic risk and poor survival. PLoS One 10: e0122992, https://doi.org/10.1371/journal.pone.0122992.Search in Google Scholar PubMed PubMed Central

Rorsman, P. and Ashcroft, F.M. (2018). Pancreatic β-cell electrical activity and insulin secretion: of mice and men. Physiol. Rev. 98: 117–214, https://doi.org/10.1152/physrev.00008.2017.Search in Google Scholar PubMed PubMed Central

Sassi, N., Marchi, U.de, Fioretti, B., Biasutto, L., Gulbins, E., Franciolini, F., Szabò, I., and Zoratti, M. (2010). An investigation of the occurrence and properties of the mitochondrial intermediate-conductance Ca2+-activated K+ channel mtKCa3.1. Biochim. Biophys. Acta 1797: 1260–1267, https://doi.org/10.1016/j.bbabio.2009.12.015.Search in Google Scholar PubMed

Sforna, L., Megaro, A., Pessia, M., Franciolini, F., and Catacuzzeno, L. (2018). Structure, gating and basic functions of the Ca2+-activated K channel of intermediate conductance. Curr. Neuropharmacol. 16: 608–617, https://doi.org/10.2174/1570159x15666170830122402.Search in Google Scholar PubMed PubMed Central

Sharma, A., Smyrk, T.C., Levy, M.J., Topazian, M.A., and Chari, S.T. (2018). Fasting blood glucose levels provide estimate of duration and progression of pancreatic cancer before diagnosis. Gastroenterology 155: 490–500.e2, https://doi.org/10.1053/j.gastro.2018.04.025.Search in Google Scholar PubMed PubMed Central

Shen, S., Gui, T., and Ma, C. (2017). Identification of molecular biomarkers for pancreatic cancer with mRMR shortest path method. Oncotarget 8: 41432–41439, https://doi.org/10.18632/oncotarget.18186.Search in Google Scholar PubMed PubMed Central

Shin, S.H., Kim, S.C., Hong, S.M., Kim, Y.H., Song, K.B., Park, K.M., and Lee, Y.J. (2013). Genetic alterations of K-ras, p53, c-erbB-2, and DPC4 in pancreatic ductal adenocarcinoma and their correlation with patient survival. Pancreas 42: 216–222, https://doi.org/10.1097/mpa.0b013e31825b6ab0.Search in Google Scholar

Sikimic, J., Hoffmeister, T., Gresch, A., Kaiser, J., Barthlen, W., Wolke, C., Wieland, I., Lendeckel, U., Krippeit-Drews, P., Düfer, M., et al.. (2020). Possible new strategies for the treatment of congenital hyperinsulinism. Front. Endocrinol. 11: 545638, https://doi.org/10.3389/fendo.2020.545638.Search in Google Scholar PubMed PubMed Central

Sperb, N., Tsesmelis, M., and Wirth, T. (2020). Crosstalk between tumor and stromal cells in pancreatic ductal adenocarcinoma. Int. J. Mol. Sci. 21: 5486, https://doi.org/10.3390/ijms21155486.Search in Google Scholar PubMed PubMed Central

Srivastava, S., Panda, S., Li, Z., Fuhs, S.R., Hunter, T., Thiele, D.J., Hubbard, S.R., and Skolnik, E.Y. (2016). Histidine phosphorylation relieves copper inhibition in the mammalian potassium channel KCa3.1. Elife 5: e16093, https://doi.org/10.7554/elife.16093.Search in Google Scholar

Staal, R.G.W., Weinstein, J.R., Nattini, M., Cajina, M., Chandresana, G., and Möller, T. (2017). Senicapoc: repurposing a drug to target microglia KCa3.1 in stroke. Neurochem. Res. 42: 2639–2645, https://doi.org/10.1007/s11064-017-2223-y.Search in Google Scholar PubMed PubMed Central

Steudel, F.A., Mohr, C.J., Stegen, B., Nguyen, H.Y., Barnert, A., Steinle, M., Beer-Hammer, S., Koch, P., Lo, W.Y., Schroth, W., et al.. (2017). SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer. Mol. Oncol. 11: 1172–1188, https://doi.org/10.1002/1878-0261.12087.Search in Google Scholar PubMed PubMed Central

Stocker, J.W., Franceschi, L.de, McNaughton-Smith, G.A., Corrocher, R., Beuzard, Y., and Brugnara, C. (2003). ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice. Blood 101: 2412–2418, https://doi.org/10.1182/blood-2002-05-1433.Search in Google Scholar PubMed

Storck, H., Hild, B., Schimmelpfennig, S., Sargin, S., Nielsen, N., Zaccagnino, A., Budde, T., Novak, I., Kalthoff, H., and Schwab, A. (2017). Ion channels in control of pancreatic stellate cell migration. Oncotarget 8: 769–784, https://doi.org/10.18632/oncotarget.13647.Search in Google Scholar PubMed PubMed Central

Strupp, M., Staub, F., and Grafe, P. (1993). A Ca2+-and pH-dependent K+ channel of rat C6 glioma cells and its possible role in acidosis-induced cell swelling. Glia 9: 136–145, https://doi.org/10.1002/glia.440090207.Search in Google Scholar PubMed

Su, X.L., Wang, Y., Zhang, W., Zhao, L.M., Li, G.R., and Deng, X.L. (2011). Insulin-mediated upregulation of K (Ca) 3.1 channels promotes cell migration and proliferation in rat vascular smooth muscle. J. Mol. Cell. Cardiol. 51: 51–57, https://doi.org/10.1016/j.yjmcc.2011.03.014.Search in Google Scholar PubMed

Sweed, D., Taha, M., Elhamed, S.A., and Mohamed, A.S.E.D. (2022). The prognostic role of CD73/A2AR expression and tumor immune response in periampullary carcinoma subtypes. Asian Pac. J. Cancer Prev. APJCP 23: 1239–1246, https://doi.org/10.31557/apjcp.2022.23.4.1239.Search in Google Scholar

Szabo, I. and Zoratti, M. (2014). Mitochondrial channels: ion fluxes and more. Physiol. Rev. 94: 519–608, https://doi.org/10.1152/physrev.00021.2013.Search in Google Scholar PubMed

Tamarina, N.A., Wang, Y., Mariotto, L., Kuznetsov, A., Bond, C., Adelman, J., and Philipson, L.H. (2003). Small-conductance calcium-activated K+ channels are expressed in pancreatic islets and regulate glucose responses. Diabetes 52: 2000–2006, https://doi.org/10.2337/diabetes.52.8.2000.Search in Google Scholar PubMed

Tao, J., Yang, G., Zhou, W., Qiu, J., Chen, G., Luo, W., Zhao, F., You, L., Zheng, L., Zhang, T., et al.. (2021). Targeting hypoxic tumor microenvironment in pancreatic cancer. J. Hematol. Oncol. 14: 14, https://doi.org/10.1186/s13045-020-01030-w.Search in Google Scholar PubMed PubMed Central

Tesch, G.H. (2008). MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy. Am. J. Physiol. Ren. Physiol. 294: F697–F701, https://doi.org/10.1152/ajprenal.00016.2008.Search in Google Scholar PubMed

Thompson-Vest, N., Shimizu, Y., Hunne, B., and Furness, J.B. (2006). The distribution of intermediate-conductance, calcium-activated, potassium (IK) channels in epithelial cells. J. Anat. 208: 219–229, https://doi.org/10.1111/j.1469-7580.2006.00515.x.Search in Google Scholar PubMed PubMed Central

Todesca, L.M., Maskri, S., Brömmel, K., Thale, I., Wünsch, B., Koch, O., and Schwab, A. (2021). Targeting Kca3.1 channels in cancer. Cell. Physiol. Biochem. 55: 131–144, https://doi.org/10.33594/000000374.Search in Google Scholar PubMed

Wang, J., Haanes, K.A., and Novak, I. (2013). Purinergic regulation of CFTR and Ca (2+)-activated Cl (-) channels and K (+) channels in human pancreatic duct epithelium. Am. J. Physiol. Cell Physiol. 304: C673–C684, https://doi.org/10.1152/ajpcell.00196.2012.Search in Google Scholar PubMed

Welsh, N., Cnop, M., Kharroubi, I., Bugliani, M., Lupi, R., Marchetti, P., and Eizirik, D.L. (2005). Is there a role for locally produced interleukin-1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets? Diabetes 54: 3238–3244, https://doi.org/10.2337/diabetes.54.11.3238.Search in Google Scholar PubMed

Wong, R. and Schlichter, L.C. (2014). PKA reduces the rat and human KCa3.1 current, CaM binding, and Ca2+ signaling, which requires Ser332/334 in the CaM-binding C terminus. J. Neurosci. 34: 13371–13383, https://doi.org/10.1523/jneurosci.1008-14.2014.Search in Google Scholar

Wulf, A. and Schwab, A. (2002). Regulation of a calcium-sensitive K+ channel (cIK1) by protein kinase C. J. Membr. Biol. 187: 71–79, https://doi.org/10.1007/s00232-001-0149-3.Search in Google Scholar PubMed

Wulff, H., Knaus, H.G., Pennington, M., and Chandy, K.G. (2004). K+ channel expression during B cell differentiation: implications for immunomodulation and autoimmunity. J. Immunol. 173: 776–786, https://doi.org/10.4049/jimmunol.173.2.776.Search in Google Scholar PubMed

Wulff, H., Miller, M.J., Hansel, W., Grissmer, S., Cahalan, M.D., and Chandy, K.G. (2000). Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+ channel, IKCa1: a potential immunosuppressant. Proc. Natl. Acad. Sci. USA 97: 8151–8156, https://doi.org/10.1073/pnas.97.14.8151.Search in Google Scholar PubMed PubMed Central

Xu, R., Li, C., Wu, Y., Shen, L., Ma, J., Qian, J., and Ge, J. (2017). Role of KCa3.1 channels in macrophage polarization and its relevance in atherosclerotic plaque instability. Arterioscler. Thromb. Vasc. Biol. 37: 226–236, https://doi.org/10.1161/atvbaha.116.308461.Search in Google Scholar PubMed

Zaccagnino, A., Pilarsky, C., Tawfik, D., Sebens, S., Trauzold, A., Novak, I., Schwab, A., and Kalthoff, H. (2016). In silico analysis of the transportome in human pancreatic ductal adenocarcinoma. Eur. Biophys. J. 45: 749–763, https://doi.org/10.1007/s00249-016-1171-9.Search in Google Scholar PubMed

Zhang, A.M.Y., Magrill, J., Winter, T.J.J.de, Hu, X., Skovsø, S., Schaeffer, D.F., Kopp, J.L., and Johnson, J.D. (2019). Endogenous hyperinsulinemia contributes to pancreatic cancer development. Cell Metabol. 30: 403–404, https://doi.org/10.1016/j.cmet.2019.07.003.Search in Google Scholar PubMed

Zhang, M., Houamed, K., Kupershmidt, S., Roden, D., and Satin, L.S. (2005). Pharmacological properties and functional role of Kslow current in mouse pancreatic beta-cells: SK channels contribute to Kslow tail current and modulate insulin secretion. J. Gen. Physiol. 126: 353–363, https://doi.org/10.1085/jgp.200509312.Search in Google Scholar PubMed PubMed Central

Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/hsz-2022-0232).

Received: 2022-07-15
Accepted: 2022-11-24
Published Online: 2022-12-27
Published in Print: 2023-03-28

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Highlight: Chemical Biology of Ion Channels
  3. Highlight: chemical biology of ion channels
  4. The second PI(3,5)P2 binding site in the S0 helix of KCNQ1 stabilizes PIP2-at the primary PI1 site with potential consequences on intermediate-to-open state transition
  5. In vitro ADME characterization of a very potent 3-acylamino-2-aminopropionic acid-derived GluN2C-NMDA receptor agonist and its ester prodrugs
  6. A novel NMDA receptor test model based on hiPSC-derived neural cells
  7. Chemical, pharmacodynamic and pharmacokinetic characterization of the GluN2B receptor antagonist 3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol – starting point for PET tracer development
  8. Characterization of Kv1.2-mediated outward current in TRIP8b-deficient mice
  9. Influence of inflammatory processes on thalamocortical activity
  10. NMDA receptors – regulatory function and pathophysiological significance for pancreatic beta cells
  11. The role of the Na+/Ca2+-exchanger (NCX) in cancer-associated fibroblasts
  12. Pancreatic KCa3.1 channels in health and disease
  13. Validation of TREK1 ion channel activators as an immunomodulatory and neuroprotective strategy in neuroinflammation
https://doi.org/10.1515/hsz-2022-0232
Keywords for this article
diabetes; islet of Langerhans; KCa3.1; KCNN4; pancreatic cancer; PDAC

Articles in the same Issue

  1. Frontmatter
  2. Highlight: Chemical Biology of Ion Channels
  3. Highlight: chemical biology of ion channels
  4. The second PI(3,5)P2 binding site in the S0 helix of KCNQ1 stabilizes PIP2-at the primary PI1 site with potential consequences on intermediate-to-open state transition
  5. In vitro ADME characterization of a very potent 3-acylamino-2-aminopropionic acid-derived GluN2C-NMDA receptor agonist and its ester prodrugs
  6. A novel NMDA receptor test model based on hiPSC-derived neural cells
  7. Chemical, pharmacodynamic and pharmacokinetic characterization of the GluN2B receptor antagonist 3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol – starting point for PET tracer development
  8. Characterization of Kv1.2-mediated outward current in TRIP8b-deficient mice
  9. Influence of inflammatory processes on thalamocortical activity
  10. NMDA receptors – regulatory function and pathophysiological significance for pancreatic beta cells
  11. The role of the Na+/Ca2+-exchanger (NCX) in cancer-associated fibroblasts
  12. Pancreatic KCa3.1 channels in health and disease
  13. Validation of TREK1 ion channel activators as an immunomodulatory and neuroprotective strategy in neuroinflammation
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2026 De Gruyter Brill
Downloaded on 7.1.2026 from https://www.degruyterbrill.com/document/doi/10.1515/hsz-2022-0232/pdf
Scroll to top button