Journal articles: 'Potassium channels, pancreatic cancer'

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Remigante, Alessia, Paolo Zuccolini, Raffaella Barbieri, Loretta Ferrera, Rossana Morabito, Paola Gavazzo, Michael Pusch, and Cristiana Picco. "NS-11021 Modulates Cancer-Associated Processes Independently of BK Channels in Melanoma and Pancreatic Duct Adenocarcinoma Cell Lines." Cancers 13, no. 23 (December 6, 2021): 6144. http://dx.doi.org/10.3390/cancers13236144.

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Potassium channels have emerged as regulators of carcinogenesis, thus introducing possible new therapeutic strategies in the fight against cancer. In particular, the large-conductance Ca2+-activated K+ channel, often referred to as BK channel, is involved in several cancer-associated processes. Here, we investigated the effects of different BK activators, NS-11021, NS-19504, and BMS-191011, in IGR39 (primary melanoma cell line) and Panc-1 (primary pancreatic duct carcinoma cell line), highly expressing the channel, and in IGR37 (metastatic melanoma cell line) that barely express BK. Our data showed that NS-11021 and NS-19504 potently activated BK channels in IGR39 and Panc-1 cells, while no effect on channel activation was detected in IGR37 cells. On the contrary, BK channel activator BMS-191011 was less effective. However, only NS-11021 showed significant effects in cancer-associated processes, such as cell survival, migration, and proliferation in these cancer cell lines. Moreover, NS-11021 led to an increase of intracellular Ca2+ concentration, independent of BK channel activation, thus complicating any interpretation of its role in the regulation of cancer-associated mechanisms. Overall, we conclude that the activation of the BK channel by itself is not sufficient to produce beneficial anti-cancer effects in the melanoma and PDAC cell lines examined. Importantly, our results raise an alarm flag regarding the use of presumably specific BK channel openers as anti-cancer agents.

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Iorio, Jessica, Lorenzo Antonuzzo, Emanuela Scarpi, Massimo D’Amico, Claudia Duranti, Luca Messerini, Clotilde Sparano, et al. "Prognostic role of hERG1 Potassium Channels in Neuroendocrine Tumours of the Ileum and Pancreas." International Journal of Molecular Sciences 23, no. 18 (September 13, 2022): 10623. http://dx.doi.org/10.3390/ijms231810623.

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hERG1 potassium channels are widely expressed in human cancers of different origins, where they affect several key aspects of cellular behaviour. The present study was designed to evaluate the expression and clinical relevance of hERG1 protein in cancer tissues from patients suffering from neuroendocrine tumours (NETs) of ileal (iNETs) and pancreatic (pNETs) origin, with available clinicopathological history and follow-up. The study was carried out by immunohistochemistry with an anti-hERG1 monoclonal antibody. In a subset of samples, a different antibody directed against the hERG1/β1 integrin complex was also used. The analysis showed for the first time that hERG1 is expressed in human NETs originating from either the ileum or the pancreas. hERG1 turned out to have a prognostic value in NETs, showing (i) a statistically significant positive impact on OS of patients affected by ileal NETs, regardless the TNM stage; (ii) a statistically significant positive impact on OS of patients affected by aggressive (TNM stage IV) disease, either ileal or pancreatic; (iii) a trend to a negative impact on OS of patients affected by less aggressive (TNM stage I-III) disease, either ileal or pancreatic. Moreover, in order to evaluate whether ERG1 was functionally expressed in a cellular model of pNET, the INS1E rat insulinoma cell line was used, and it emerged that blocking ERG1 with a specific inhibitor of the channel (E4031) turned out in a significant reduction in cell proliferation.

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Manoli, Sagar, Stefano Coppola, Claudia Duranti, Matteo Lulli, Lara Magni, Nirmala Kuppalu, Nikolaj Nielsen, et al. "The Activity of Kv 11.1 Potassium Channel Modulates F-Actin Organization During Cell Migration of Pancreatic Ductal Adenocarcinoma Cells." Cancers 11, no. 2 (January 23, 2019): 135. http://dx.doi.org/10.3390/cancers11020135.

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Cell migration exerts a pivotal role in tumor progression, underlying cell invasion and metastatic spread. The cell migratory program requires f-actin re-organization, generally coordinated with the assembly of focal adhesions. Ion channels are emerging actors in regulating cell migration, through different mechanisms. We studied the role of the voltage dependent potassium channel KV 11.1 on cell migration of pancreatic ductal adenocarcinoma (PDAC) cells, focusing on its effects on f-actin organization and dynamics. Cells were cultured either on fibronectin (FN) or on a desmoplastic matrix (DM) with the addition of a conditioned medium produced by pancreatic stellate cells (PSC) maintained in hypoxia (Hypo-PSC-CM), to better mimic the PDAC microenvironment. KV11.1 was essential to maintain stress fibers in a less organized arrangement in cells cultured on FN. When PDAC cells were cultured on DM plus Hypo-PSC-CM, KV11.1 activity determined the organization of cortical f-actin into sparse and long filopodia, and allowed f-actin polymerization at a high speed. In both conditions, blocking KV11.1 impaired PDAC cell migration, and, on cells cultured onto FN, the effect was accompanied by a decrease of basal intracellular Ca2+ concentration. We conclude that KV11.1 is implicated in sustaining pro-metastatic signals in pancreatic cancer, through a reorganization of f-actin in stress fibers and a modulation of filopodia formation and dynamics.

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Jiang, Shuheng, Lili Zhu, Jianyu Yang, Lipeng Hu, Jianren Gu, Xin Xing, Yongwei Sun, and Zhigang Zhang. "Integrated expression profiling of potassium channels identifys KCNN4 as a prognostic biomarker of pancreatic cancer." Biochemical and Biophysical Research Communications 494, no. 1-2 (December 2017): 113–19. http://dx.doi.org/10.1016/j.bbrc.2017.10.072.

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Wei, Mengyan, Pu Wang, Xiufang Zhu, Masaki Morishima, Yangong Liu, Mingqi Zheng, Gang Liu, et al. "Electrophysiological evaluation of an anticancer drug gemcitabine on cardiotoxicity revealing down-regulation and modification of the activation gating properties in the human rapid delayed rectifier potassium channel." PLOS ONE 18, no. 2 (February 2, 2023): e0280656. http://dx.doi.org/10.1371/journal.pone.0280656.

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Gemcitabine is an antineoplastic drug commonly used in the treatment of several types of cancers including pancreatic cancer and non–small cell lung cancer. Although gemcitabine-induced cardiotoxicity is widely recognized, the exact mechanism of cardiac dysfunction causing arrhythmias remains unclear. The objective of this study was to electrophysiologically evaluate the proarrhythmic cardiotoxicity of gemcitabine focusing on the human rapid delayed rectifier potassium channel, hERG channel. In heterologous hERG expressing HEK293 cells (hERG-HEK cells), hERG channel current (IhERG) was reduced by gemcitabine when applied for 24 h but not immediately after the application. Gemcitabine modified the activation gating properties of the hERG channel toward the hyperpolarization direction, while inactivation, deactivation or reactivation gating properties were unaffected by gemcitabine. When gemcitabine was applied to hERG-HEK cells in combined with tunicamycin, an inhibitor of N-acetylglucosamine phosphotransferase, gemcitabine was unable to reduce IhERG or shift the activation properties toward the hyperpolarization direction. While a mannosidase I inhibitor kifunensine alone reduced IhERG and the reduction was even larger in combined with gemcitabine, kifunensine was without effect on IhERG when hERG-HEK cells were pretreated with gemcitabine for 24 h. In addition, gemcitabine down-regulated fluorescence intensity for hERG potassium channel protein in rat neonatal cardiomyocyte, although hERG mRNA was unchanged. Our results suggest the possible mechanism of arrhythmias caused by gemcitabine revealing a down-regulation of IhERG through the post-translational glycosylation disruption possibly at the early phase of hERG channel glycosylation in the endoplasmic reticulum that alters the electrical excitability of cells.

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Xu, Rui, Qiuyan Xu, Guanglei Huang, Xinhai Yin, Jianguo Zhu, Yikun Peng, and Jukun Song. "Combined Analysis of the Aberrant Epigenetic Alteration of Pancreatic Ductal Adenocarcinoma." BioMed Research International 2019 (December 28, 2019): 1–11. http://dx.doi.org/10.1155/2019/9379864.

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Background. Pancreatic ductal adenocarcinoma (PDAC) remains one of the most fatal malignancies due to its high morbidity and mortality. DNA methylation exerts a vital part in the development of PDAC. However, a mechanistic role of mutual interactions between DNA methylation and mRNA as epigenetic regulators on transcriptomic alterations and its correlation with clinical outcomes such as survival have remained largely uncovered in cancer. Therefore, elucidation of aberrant epigenetic alteration in the development of PDAC is an urgent problem to be solved. In this work, we conduct an integrative epigenetic analysis of PDAC to identify aberrant DNA methylation-driven cancer genes during the occurrence of cancer. Methods. DNA methylation matrix and mRNA profile were obtained from the TCGA database. The integration of methylation and gene expression datasets was analyzed using an R package MethylMix. The genes with hypomethylation/hypermethylation were further validated in the Kaplan–Meier analysis. The correlation analysis of gene expression and aberrant DNA methylation was also conducted. We performed a pathway analysis on aberrant DNG methylation genes identified by MethylMix criteria using ConsensusPathDB. Results. 188 patients with both methylation data and mRNA data were considered eligible. A mixture model was constructed, and differential methylation genes in normal and tumor groups using the Wilcoxon rank test was performed. With the inclusion criteria, 95 differential methylation genes were detected. Among these genes, 74 hypermethylation and 21 hypomethylation genes were found. The pathway analysis revealed an increase in hypermethylation of genes involved in ATP-sensitive potassium channels, Robo4, and VEGF signaling pathways crosstalk, and generic transcription pathway. Conclusion. Integrated analysis of the aberrant epigenetic alteration in pancreatic ductal adenocarcinoma indicated that differentially methylated genes could play a vital role in the occurrence of PDAC by bioinformatics analysis. The present work can help clinicians to elaborate on the function of differentially methylated expressed genes and pathways in PDAC. CDO1, GJD2, ID4, NOL4, PAX6, TRIM58, and ZNF382 might act as aberrantly DNA-methylated biomarkers for early screening and therapy of PDAC in the future.

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Li, Weiwei, Gregory C. Wilson, Magdalena Bachmann, Jiang Wang, Andrea Mattarei, Cristina Paradisi, Michael J. Edwards, et al. "Inhibition of a Mitochondrial Potassium Channel in Combination with Gemcitabine and Abraxane Drastically Reduces Pancreatic Ductal Adenocarcinoma in an Immunocompetent Orthotopic Murine Model." Cancers 14, no. 11 (May 25, 2022): 2618. http://dx.doi.org/10.3390/cancers14112618.

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Pancreas ductal adenocarcinoma (PDAC) is one the most aggressive cancers and associated with very high mortality, requiring the development of novel treatments. The mitochondrial voltage-gated potassium channel, Kv1.3 is emerging as an attractive oncologic target but its function in PDAC is unknown. Here, we evaluated the tissue expression of Kv1.3 in resected PDAC from 55 patients using immunohistochemistry (IHC) and show that all tumors expressed Kv1.3 with 60% of tumor specimens having high Kv1.3 expression. In Pan02 cells, the recently developed mitochondria-targeted Kv1.3 inhibitors PCARBTP and PAPTP strongly reduced cell survival in vitro. In an orthotopic pancreas tumor model (Pan02 cells injected into C57BL/6 mice) in immune-competent mice, injection of PAPTP or PCARBTP resulted in tumor reductions of 87% and 70%, respectively. When combined with clinically used Gemcitabine plus Abraxane (albumin-bound paclitaxel), reduction reached 95% and 80% without resultant organ toxicity. Drug-mediated tumor cell death occurred through the p38-MAPK pathway, loss of mitochondrial membrane potential, and oxidative stress. Resistant Pan02 clones to PCARBTP escaped cell death through upregulation of the antioxidant system. In contrast, tumor cells did not develop resistance to PAPTP. Our data show that Kv1.3 is highly expressed in resected human PDAC and the use of novel mitochondrial Kv1.3 inhibitors combined with cytotoxic chemotherapies might be a novel, effective treatment for PDAC.

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Huang, Xi, and Lily Yeh Jan. "Targeting potassium channels in cancer." Journal of Cell Biology 206, no. 2 (July 21, 2014): 151–62. http://dx.doi.org/10.1083/jcb.201404136.

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Potassium channels are pore-forming transmembrane proteins that regulate a multitude of biological processes by controlling potassium flow across cell membranes. Aberrant potassium channel functions contribute to diseases such as epilepsy, cardiac arrhythmia, and neuromuscular symptoms collectively known as channelopathies. Increasing evidence suggests that cancer constitutes another category of channelopathies associated with dysregulated channel expression. Indeed, potassium channel–modulating agents have demonstrated antitumor efficacy. Potassium channels regulate cancer cell behaviors such as proliferation and migration through both canonical ion permeation–dependent and noncanonical ion permeation–independent functions. Given their cell surface localization and well-known pharmacology, pharmacological strategies to target potassium channel could prove to be promising cancer therapeutics.

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Huang, Xi, and Lily Yeh Jan. "Targeting potassium channels in cancer." Journal of General Physiology 144, no. 2 (July 28, 2014): 1442OIA34. http://dx.doi.org/10.1085/jgp.1442oia34.

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Hayashi, Mikio, and Ivana Novak. "Molecular basis of potassium channels in pancreatic duct epithelial cells." Channels 7, no. 6 (November 2, 2013): 432–41. http://dx.doi.org/10.4161/chan.26100.

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Sharma, Nidhi, Ana Crane, Gabriela Gonzalez, Joseph Bryan, and Lydia Aguilar-Bryan. "Familial hyperinsulinism and pancreatic β-cell ATP-sensitive potassium channels." Kidney International 57, no. 3 (March 2000): 803–8. http://dx.doi.org/10.1046/j.1523-1755.2000.00918.x.

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Schmid, A., and I. Schulz. "Characterization of single potassium channels in mouse pancreatic acinar cells." Journal of Physiology 484, no. 3 (May 1, 1995): 661–76. http://dx.doi.org/10.1113/jphysiol.1995.sp020694.

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Cruz-Cruz, Iskra, Germán Bernate-Obando, Carlos Larqué, Rene Escalona, Rodolfo Pinto-Almazán, and Myrian Velasco. "Early Effects of Metabolic Syndrome on ATP-Sensitive Potassium Channels from Rat Pancreatic Beta Cells." Metabolites 12, no. 4 (April 18, 2022): 365. http://dx.doi.org/10.3390/metabo12040365.

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Metabolic syndrome (MS) is a cluster of metabolic signs that increases the risk of developing type 2 two diabetes mellitus and cardiovascular diseases. MS leads to pancreatic beta cell exhaustion and decreased insulin secretion through unknown mechanisms in a time-dependent manner. ATP-sensitive potassium channels (KATP channels), common targets of anti-diabetic drugs, participate in the glucose-stimulated insulin secretion, coupling the metabolic status and electrical activity of pancreatic beta cells. We investigated the early effects of MS on the conductance, ATP and glybenclamide sensitivity of the KATP channels. We used Wistar rats fed with a high-sucrose diet (HSD) for 8 weeks as a MS model. In excised membrane patches, control and HSD channels showed similar unitary conductance and ATP sensitivity pancreatic beta cells in their KATP channels. In contrast, MS produced variability in the sensitivity to glybenclamide of KATP channels. We observed two subpopulations of pancreatic beta cells, one with similar (Gly1) and one with increased (Gly2) glybenclamide sensitivity compared to the control group. This study shows that the early effects of MS produced by consuming high-sugar beverages can affect the pharmacological properties of KATP channels to one of the drugs used for diabetes treatment.

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Felipe, Antonio, Rubén Vicente, Núria Villalonga, Meritxell Roura-Ferrer, Ramón Martínez-Mármol, Laura Solé, Joan C. Ferreres, and Enric Condom. "Potassium channels: New targets in cancer therapy." Cancer Detection and Prevention 30, no. 4 (January 2006): 375–85. http://dx.doi.org/10.1016/j.cdp.2006.06.002.

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Packey, Christopher D., Robert M. Wilechansky, Ali S. Khan, Stuart P. Weisberg, John A. Chabot, and Tamas A. Gonda. "Pancreatic Neuroendocrine Tumor Associated With Antibodies to Voltage-Gated Potassium Channels." Pancreas 45, no. 8 (September 2016): e42-e43. http://dx.doi.org/10.1097/mpa.0000000000000651.

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Camacho, Javier. "Ether à go-go potassium channels and cancer." Cancer Letters 233, no. 1 (February 2006): 1–9. http://dx.doi.org/10.1016/j.canlet.2005.02.016.

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Pardo, L. A., C. Contreras-Jurado, M. Zientkowska, F. Alves, and W. Stühmer. "Role of Voltage-gated Potassium Channels in Cancer." Journal of Membrane Biology 205, no. 3 (June 2005): 115–24. http://dx.doi.org/10.1007/s00232-005-0776-1.

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Hayashi, Mikio, Jing Wang, Susanne E. Hede, and Ivana Novak. "An intermediate-conductance Ca2+-activated K+ channel is important for secretion in pancreatic duct cells." American Journal of Physiology-Cell Physiology 303, no. 2 (July 15, 2012): C151—C159. http://dx.doi.org/10.1152/ajpcell.00089.2012.

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Potassium channels play a vital role in maintaining the membrane potential and the driving force for anion secretion in epithelia. In pancreatic ducts, which secrete bicarbonate-rich fluid, the identity of K+ channels has not been extensively investigated. In this study, we investigated the molecular basis of functional K+ channels in rodent and human pancreatic ducts (Capan-1, PANC-1, and CFPAC-1) using molecular and electrophysiological techniques. RT-PCR analysis revealed mRNAs for KCNQ1, KCNH2, KCNH5, KCNT1, and KCNT2, as well as KCNN4 coding for the following channels: KVLQT1; HERG; EAG2; Slack; Slick; and an intermediate-conductance Ca2+-activated K+ (IK) channel (KCa3.1). The following functional studies were focused on the IK channel. 5,6-Dichloro-1-ethyl-1,3-dihydro-2 H-benzimidazole-2-one (DC-EBIO), an activator of IK channel, increased equivalent short-circuit current ( Isc) in Capan-1 monolayer, consistent with a secretory response. Clotrimazole, a blocker of IK channel, inhibited Isc. IK channel blockers depolarized the membrane potential of cells in microperfused ducts dissected from rodent pancreas. Cell-attached patch-clamp single-channel recordings revealed IK channels with an average conductance of 80 pS in freshly isolated rodent duct cells. These results indicated that the IK channels may, at least in part, be involved in setting the resting membrane potential. Furthermore, the IK channels are involved in anion and potassium transport in stimulated pancreatic ducts.

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Yan, L., D. J. Figueroa, C. P. Austin, Y. Liu, R. M. Bugianesi, R. S. Slaughter, G. J. Kaczorowski, and M. G. Kohler. "Expression of Voltage-Gated Potassium Channels in Human and Rhesus Pancreatic Islets." Diabetes 53, no. 3 (February 26, 2004): 597–607. http://dx.doi.org/10.2337/diabetes.53.3.597.

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Kukuljan, Manuel, Min Yi Li, and Illani Atwater. "Characterization of potassium channels in pancreatic β cells from ob /ob mice." FEBS Letters 266, no. 1-2 (June 18, 1990): 105–8. http://dx.doi.org/10.1016/0014-5793(90)81518-s.

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Dadi, Prasanna, Brooke Luo, and David Jacobson. "Two-Pore-Domain TASK-1 Potassium Channels Modulate Pancreatic Islet Glucagon Secretion." Biophysical Journal 106, no. 2 (January 2014): 552a. http://dx.doi.org/10.1016/j.bpj.2013.11.3072.

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Schwanstecher, C., and M. Schwanstecher. "Nucleotide Sensitivity of Pancreatic ATP-Sensitive Potassium Channels and Type 2 Diabetes." Diabetes 51, Supplement 3 (December 1, 2002): S358—S362. http://dx.doi.org/10.2337/diabetes.51.2007.s358.

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Wrzosek, Antoni, Bartłomiej Augustynek, Monika Żochowska, and Adam Szewczyk. "Mitochondrial Potassium Channels as Druggable Targets." Biomolecules 10, no. 8 (August 18, 2020): 1200. http://dx.doi.org/10.3390/biom10081200.

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Mitochondrial potassium channels have been described as important factors in cell pro-life and death phenomena. The activation of mitochondrial potassium channels, such as ATP-regulated or calcium-activated large conductance potassium channels, may have cytoprotective effects in cardiac or neuronal tissue. It has also been shown that inhibition of the mitochondrial Kv1.3 channel may lead to cancer cell death. Hence, in this paper, we examine the concept of the druggability of mitochondrial potassium channels. To what extent are mitochondrial potassium channels an important, novel, and promising drug target in various organs and tissues? The druggability of mitochondrial potassium channels will be discussed within the context of channel molecular identity, the specificity of potassium channel openers and inhibitors, and the unique regulatory properties of mitochondrial potassium channels. Future prospects of the druggability concept of mitochondrial potassium channels will be evaluated in this paper.

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Rubaiy, Hussein N. "The therapeutic agents that target ATP-sensitive potassium channels." Acta Pharmaceutica 66, no. 1 (March 1, 2016): 23–34. http://dx.doi.org/10.1515/acph-2016-0006.

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AbstractATP-sensitive potassium (KATP) channels are a major drug target for the treatment of type-2 diabetes. KATPchannels are ubiquitously expressed and link the metabolic state to electrical excitability. In pancreatic β-cells, KATPchannels are crucial in the regulation of glucose-induced insulin secretion. Also, KATPchannels are involved in the protection against neuronal seizures and ischaemic stress in the heart, brain and in the regulation of vascular smooth muscle tone. Functional KATPchannels are hetero-octamers composed of two subunits, a pore forming Kir6, which is a member of the inwardly rectifying potassium channels family, and a regulatory sulphonylurea receptor (SUR). In response to nucleotides and pharmaceutical agonists and antagonists, SUR allosterically regulates channel gating. The allosteric communication pathways between these two heterologus proteins in KATPchannels are still poorly understood. This review will highlight the therapeutic agents that target KATPchannels and are used to treat diabetes and cardiovascular diseases.

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Ibrahim, Dakik, Vandier, Chautard, Paintaud, Mazurier, Lecomte, Guéguinou, and Raoul. "Expression Profiling of Calcium Channels and Calcium-Activated Potassium Channels in Colorectal Cancer." Cancers 11, no. 4 (April 19, 2019): 561. http://dx.doi.org/10.3390/cancers11040561.

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Background: Colorectal cancer (CRC) is a highly devastating cancer. Ca2+-dependent channels are now considered key regulators of tumor progression. In this study, we aimed to investigate the association of non-voltage gated Ca2+ channels and Ca2+-dependent potassium channels (KCa) with CRC using the transcriptional profile of their genes. Methods: We selected a total of 35 genes covering KCa channels KCNN1–4, KCNMA1 and their subunits KCNMB1–4, endoplasmic reticulum (ER) calcium sensors STIM1 and STIM2, Ca2+ channels ORAI1–3 and the family of cation channels TRP (TRPC1–7, TRPA1, TRPV1/2,4–6 and TRPM1–8). We analyzed their expression in two public CRC datasets from The Cancer Genome Atlas (TCGA) and GSE39582. Results: KCNN4 and TRPM2 were induced while KCNMA1 and TRPM6 were downregulated in tumor tissues comparing to normal tissues. In proximal tumors, STIM2 and KCNN2 were upregulated while ORAI2 and TRPM6 were downregulated. ORAI1 decreased in lymph node metastatic tumors. TRPC1 and ORAI3 predicted poor prognosis in CRC patients. Moreover, we found that ORAI3/ORAI1 ratio is increased in CRC progression and predicted poor prognosis. Conclusions: KCa and Ca2+ channels could be important contributors to CRC initiation and progression. Our results provide new insights on KCa and Ca2+ channels remodeling in CRC.

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Yan, Fei-Fei, Chia-Wei Lin, Etienne A. Cartier, and Show-Ling Shyng. "Role of ubiquitin-proteasome degradation pathway in biogenesis efficiency of β-cell ATP-sensitive potassium channels." American Journal of Physiology-Cell Physiology 289, no. 5 (November 2005): C1351—C1359. http://dx.doi.org/10.1152/ajpcell.00240.2005.

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ATP-sensitive potassium (KATP) channels of pancreatic β-cells mediate glucose-induced insulin secretion by linking glucose metabolism to membrane excitability. The number of plasma membrane KATP channels determines the sensitivity of β-cells to glucose stimulation. The KATP channel is formed in the endoplasmic reticulum (ER) on coassembly of four inwardly rectifying potassium channel Kir6.2 subunits and four sulfonylurea receptor 1 (SUR1) subunits. Little is known about the cellular events that govern the channel's biogenesis efficiency and expression. Recent studies have implicated the ubiquitin-proteasome pathway in modulating surface expression of several ion channels. In this work, we investigated whether the ubiquitin-proteasome pathway plays a role in the biogenesis efficiency and surface expression of KATP channels. We provide evidence that, when expressed in COS cells, both Kir6.2 and SUR1 undergo ER-associated degradation via the ubiquitin-proteasome system. Moreover, treatment of cells with proteasome inhibitors MG132 or lactacystin leads to increased surface expression of KATP channels by increasing the efficiency of channel biogenesis. Importantly, inhibition of proteasome function in a pancreatic β-cell line, INS-1, that express endogenous KATP channels also results in increased channel number at the cell surface, as assessed by surface biotinylation and whole cell patch-clamp recordings. Our results support a role of the ubiquitin-proteasome pathway in the biogenesis efficiency and surface expression of β-cell KATP channels.

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Kusunoki, Munenori, Mikio Hayashi, Tomohiro Shoji, Takeo Uba, Hiromasa Tanaka, Chisato Sumi, Yoshiyuki Matsuo, and Kiichi Hirota. "Propofol inhibits stromatoxin-1-sensitive voltage-dependent K+ channels in pancreatic β-cells and enhances insulin secretion." PeerJ 7 (December 2, 2019): e8157. http://dx.doi.org/10.7717/peerj.8157.

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Background Proper glycemic control is an important goal of critical care medicine, including perioperative patient care that can influence patients’ prognosis. Insulin secretion from pancreatic β-cells is generally assumed to play a critical role in glycemic control in response to an elevated blood glucose concentration. Many animal and human studies have demonstrated that perioperative drugs, including volatile anesthetics, have an impact on glucose-stimulated insulin secretion (GSIS). However, the effects of the intravenous anesthetic propofol on glucose metabolism and insulin sensitivity are largely unknown at present. Methods The effect of propofol on insulin secretion under low glucose or high glucose was examined in mouse MIN6 cells, rat INS-1 cells, and mouse pancreatic β-cells/islets. Cellular oxygen or energy metabolism was measured by Extracellular Flux Analyzer. Expression of glucose transporter 2 (GLUT2), potassium channels, and insulin mRNA was assessed by qRT-PCR. Protein expression of voltage-dependent potassium channels (Kv2) was also assessed by immunoblot. Propofol’s effects on potassium channels including stromatoxin-1-sensitive Kv channels and cellular oxygen and energy metabolisms were also examined. Results We showed that propofol, at clinically relevant doses, facilitates insulin secretion under low glucose conditions and GSIS in MIN6, INS-1 cells, and pancreatic β-cells/islets. Propofol did not affect intracellular ATP or ADP concentrations and cellular oxygen or energy metabolism. The mRNA expression of GLUT2 and channels including the voltage-dependent calcium channels Cav1.2, Kir6.2, and SUR1 subunit of KATP, and Kv2 were not affected by glucose or propofol. Finally, we demonstrated that propofol specifically blocks Kv currents in β-cells, resulting in insulin secretion in the presence of glucose. Conclusions Our data support the hypothesis that glucose induces membrane depolarization at the distal site, leading to KATP channel closure, and that the closure of Kv channels by propofol depolarization in β-cells enhances Ca2+ entry, leading to insulin secretion. Because its activity is dependent on GSIS, propofol and its derivatives are potential compounds that enhance and initiate β-cell electrical activity.

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Zhao, Yu-Feng, Li Wang, Dingjun Zha, Li Qiao, Lianjun Lu, Jun Yu, Ping Qu, Qiang Sun, Jianhua Qiu, and Chen Chen. "GW9508 inhibits insulin secretion by activating ATP-sensitive potassium channels in rat pancreatic β-cells." Journal of Molecular Endocrinology 51, no. 1 (April 29, 2013): 69–77. http://dx.doi.org/10.1530/jme-13-0019.

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GW9508 is an agonist of G protein-coupled receptor 40 (GPR40) that is expressed in pancreatic β-cells and is reported to regulate insulin secretion. However, the effects of GW9508 on pancreatic β-cells in primary culture have not been well investigated. This study measured the acute effects of GW9508 on insulin secretion from rat pancreatic islets in primary culture, and the insulin secretion-related events such as the changes in membrane potential, ATP-sensitive potassium currents (KATP currents), and intracellular Ca2+ concentrations ([Ca2+]i) of rat islet β-cells were also recorded. GW9508 (10–40 μM) did not influence basal insulin levels at 2 mM glucose, but it (above 20 μM) significantly inhibited 5 and 15 mM glucose-stimulated insulin secretion (GSIS). GW9508 did not inhibit insulin secretion stimulated by tolbutamide, the closer of KATP channels. GW9508 activated KATP channels and blocked the membrane depolarization and the increase in [Ca2+]i that were stimulated by glucose. GW9508 itself stimulated a transient increase in [Ca2+]i, which was fully blocked by depletion of intracellular Ca2+ stores with thapsigargin or by inhibition of phospholipase C (PLC) activity with U73122. GW9508-induced activation of KATP channels was only partly inhibited by U73122 treatment. In conclusion, although it stimulates a transient release of Ca2+ from intracellular Ca2+ stores via activation of PLC, GW9508 inhibits GSIS by activating KATP channels probably in a distal step to GPR40 activation in rat β-cells.

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Ashcroft, F. M., S. J. Ashcroft, and D. E. Harrison. "Properties of single potassium channels modulated by glucose in rat pancreatic beta-cells." Journal of Physiology 400, no. 1 (June 1, 1988): 501–27. http://dx.doi.org/10.1113/jphysiol.1988.sp017134.

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Dadi, Prasanna K., Brooke Luo, Nicholas C. Vierra, and David A. Jacobson. "TASK-1 Potassium Channels Limit Pancreatic α-Cell Calcium Influx and Glucagon Secretion." Molecular Endocrinology 29, no. 5 (May 1, 2015): 777–87. http://dx.doi.org/10.1210/me.2014-1321.

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Venglovecz, Viktoria, Peter Hegyi, Zoltan Rakonczay, Barry Argent, and Michael A. Gray. "Bile Acids Selectively Activate Iberiotoxin-sensitive Potassium Channels In Native Pancreatic Duct Cells." Biophysical Journal 96, no. 3 (February 2009): 536a—537a. http://dx.doi.org/10.1016/j.bpj.2008.12.2769.

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Venglovecz, Viktória, Zoltán Rakonczay, Michael A. Gray, and Péter Hegyi. "Potassium channels in pancreatic duct epithelial cells: their role, function and pathophysiological relevance." Pflügers Archiv - European Journal of Physiology 467, no. 4 (July 31, 2014): 625–40. http://dx.doi.org/10.1007/s00424-014-1585-0.

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Sivaprasadarao, A., T. K. Taneja, J. Mankouri, and A. J. Smith. "Trafficking of ATP-sensitive potassium channels in health and disease." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 1055–59. http://dx.doi.org/10.1042/bst0351055.

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KATP channels (ATP-sensitive potassium channels), comprising four subunits each of Kir6.2 (inwardly rectifying potassium channel 6.2) and the SUR1 (sulfonylurea receptor 1), play a central role in glucose-stimulated insulin secretion by the pancreatic β-cell. Changes in the number of channels at the cell surface are associated with genetic diseases of aberrant insulin secretion, including CHI (congenital hyperinsulinism) and NDM (neonatal diabetes mellitus). The present review summarizes advances in our understanding of the vesicular trafficking of normal KATP channels and how genetic mutations in Kir6.2 interfere with such trafficking. A mutation, E282K, causing CHI, was found to disrupt a DXE [di-acidic ER (endoplasmic reticulum)-exit signal], thereby preventing its assembly into COPII (coatamer protein II)-coated vesicles and subsequent ER exit. The resultant decrease in the cell-surface density of the channel could explain the disease phenotype. Two mutations, Y330C and F333I, reported in patients with NDM, disrupted an endocytic traffic signal, thereby impairing CCV (clathrin-coated vesicle) formation and endocytosis. The consequent increase in the density of KATP channels, together with an attenuated sensitivity to ATP reported previously, may account for the severe form of NDM.

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Wrzosek, Antoni, Shur Gałecka, Monika Żochowska, Anna Olszewska, and Bogusz Kulawiak. "Alternative Targets for Modulators of Mitochondrial Potassium Channels." Molecules 27, no. 1 (January 4, 2022): 299. http://dx.doi.org/10.3390/molecules27010299.

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Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and synthesis of reactive oxygen species (ROS). It has been found that pharmacological activation of mitochondrial potassium channels during ischemia/reperfusion (I/R) injury activates cytoprotective mechanisms resulting in increased cell survival. In cancer cells, the inhibition of these channels leads to increased cell death. Therefore, mitochondrial potassium channels are intriguing targets for the development of new pharmacological strategies. In most cases, however, the substances that modulate the mitochondrial potassium channels have a few alternative targets in the cell. This may result in unexpected or unwanted effects induced by these compounds. In our review, we briefly present the various classes of mitochondrial potassium (mitoK) channels and describe the chemical compounds that modulate their activity. We also describe examples of the multidirectional activity of the activators and inhibitors of mitochondrial potassium channels.

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Hivelin, Céline, Sophie Béraud-Dufour, Christelle Devader, Amar Abderrahmani, Sébastien Moreno, Hamid Moha ou Maati, Alaeddine Djillani, et al. "Potentiation of Calcium Influx and Insulin Secretion in Pancreatic Beta Cell by the Specific TREK-1 Blocker Spadin." Journal of Diabetes Research 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/3142175.

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Inhibition of the potassium channels TREK-1 by spadin (SPA) is currently thought to be a promising therapeutic target for the treatment of depression. Since these channels are expressed in pancreatic β-cells, we investigated their role in the control of insulin secretion and glucose homeostasis. In this study, we confirmed the expression of TREK-1 channels in the insulin secreting MIN6-B1 β-cell line and in mouse islets. We found that their blockade by SPA potentiated insulin secretion induced by potassium chloride dependent membrane depolarization. Inhibition of TREK-1 by SPA induced a decrease of the resting membrane potential (ΔVm~12 mV) and increased the cytosolic calcium concentration. In mice, administration of SPA enhanced the plasma insulin level stimulated by glucose, confirming its secretagogue effect observed in vitro. Taken together, this work identifies SPA as a novel potential pharmacological agent able to control insulin secretion and glucose homeostasis.

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Petersen, O. H., I. Findlay, K. Suzuki, and M. J. Dunne. "Messenger-mediated control of potassium channels in secretory cells." Journal of Experimental Biology 124, no. 1 (September 1, 1986): 33–52. http://dx.doi.org/10.1242/jeb.124.1.33.

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In exocrine acinar cells (pancreas, salivary gland, lacrimal gland) stimulation with hormones or neurotransmitters evokes K+ loss due to opening of K+ channels in the plasma membrane whereas in the insulin-secreting pancreatic beta-cells, stimulation with glucose or glyceraldehyde evokes membrane depolarization due to closure of K+ channels. By measuring directly the small K+ currents flowing through single channels, in electrically isolated patches of plasma membrane of intact cells, it can be shown that stimulants having no direct access to the small membrane area from which recording is made can influence the pattern of channel opening. In the case of hormonal activation of exocrine acinar cells, Ca2+ is the final messenger and the K+-selective channel involved in the response has a high unit conductance, is very voltage sensitive and can be blocked by external tetraethylammonium. In the case of the insulin-secreting cells, the K+ channel which is inhibited by metabolic stimulation is a voltage-insensitive, inward rectifier which can be blocked by quinine. In experiments on permeabilized cells or cell-free excised, inside-out, membrane patches it can be shown that ATP evokes channel closure and ATP produced by glycolysis may therefore function as the internal messenger.

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Links, T. P., A. J. Smit, H. J. G. H. Oosterhuis, and W. D. Reitsma. "Potassium Channels in Hypokalaemic Periodic Paralysis: A Key to the Pathogenesis?" Clinical Science 85, no. 3 (September 1, 1993): 319–25. http://dx.doi.org/10.1042/cs0850319.

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1. A possible role for the ATP-sensitive potassium channels in the pathogenesis of hypokalaemic periodic paralysis was investigated. 2. We assessed insulin release and muscle strength after intravenous glucose loading with and without the potassium channel opener pinacidil and the potassium channel blocker glibenclamide in three patients with hypokalaemic periodic paralysis and in a pair of matched control subjects for each patient. 3. A significantly higher initial insulin response (1.5-30 min) was found in the patients with hypokalaemic periodic paralysis in comparison with the control subjects. During potassium channel blocking with glibenclamide the insulin release was more enhanced in patients than in control subjects. On the other hand, the potassium channel opener pinacidil impaired the insulin release in healthy control subjects but not in patients. The serum glucose levels showed no differences between patients and control subjects. In one of the patients with hypokalaemic periodic paralysis glucose loading resulted in a fall in muscle strength, which did not occur during the administration of pinacidil. 4. These findings suggest a disturbance in the ATP-sensitive potassium channel in patients with hypokalaemic periodic paralysis, which is not limited to pancreatic β cells, but may be also involved in the abnormal behaviour of skeletal muscle.

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AGUILAR-BRYAN, LYDIA, JOHN P. CLEMENT, GABRIELA GONZALEZ, KUMUD KUNJILWAR, ANDREY BABENKO, and JOSEPH BRYAN. "Toward Understanding the Assembly and Structure of KATP Channels." Physiological Reviews 78, no. 1 (January 1, 1998): 227–45. http://dx.doi.org/10.1152/physrev.1998.78.1.227.

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Aguilar-Bryan, Lydia, John P. Clement IV, Gabriela Gonzalez, Kumud Kunjilwar, Andrey Babenko, and Joseph Bryan. Toward Understanding the Assembly and Structure of KATP Channels. Physiol. Rev. 78: 227–245, 1998. — Adenosine 5′-triphosphate-sensitive potassium (KATP) channels couple metabolic events to membrane electrical activity in a variety of cell types. The cloning and reconstitution of the subunits of these channels demonstrate they are heteromultimers of inwardly rectifying potassium channel subunits (KIR6.x) and sulfonylurea receptors (SUR), members of the ATP-binding cassette (ABC) superfamily. Recent studies indicate that SUR and KIR6.x associate with 1:1 stoichiometry to assemble a large tetrameric channel, (SUR/KIR6.x)4 . The KIR6.x subunits form the channel pore, whereas SUR is required for activation and regulation. Two KIR6.x genes and two SUR genes have been identified, and combinations of subunits give rise to KATP channel subtypes found in pancreatic β-cells, neurons, and cardiac, skeletal, and smooth muscle. Mutations in both the SUR1 and KIR6.2 genes have been shown to cause familial hyperinsulinism, indicating the importance of the pancreatic β-cell channel in the regulation of insulin secretion. The availability of cloned KATP channel genes opens the way for characterization of this family of ion channels and identification of additional genetic defects.

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Gasser, K. W., and J. R. Holda. "ATP-sensitive potassium transport by pancreatic secretory granule membrane." American Journal of Physiology-Gastrointestinal and Liver Physiology 264, no. 1 (January 1, 1993): G137—G142. http://dx.doi.org/10.1152/ajpgi.1993.264.1.g137.

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Electrolyte transport pathways in the pancreatic secretory granules may contribute to acini fluid production after fusion with the apical membrane. A component of this granule transport is a K(+)-selective pathway that has been measured indirectly by ionophore-induced lysis of the isolated secretory granules when suspended in a KCl solution. This granule membrane K+ transport was shown to be inhibited by physiological levels of ATP in a dose-dependent manner and was not reversed by ADP. The sulfonylurea tolbutamide (0.5 mM), a recognized inhibitor of ATP-sensitive K+ channels, also reduced the ionophore-dependent lysis by 46%. The ATP sensitivity of the K+ transport was influenced by pH (increased ATP sensitivity with decreasing pH) and KCl concentration (increased ATP sensitivity with increasing KCl). In addition, preincubation with phospholipase A2 (8.3 x 10(-10) g/ml) or lysophospholipids (6.7 x 10(-7) g/ml) produced a significant decrease in the granule K+ transport. However, it is not likely that this inhibition is due to a change in membrane fluidity, because fluidization with arachidonic acid or octanol did not have a comparable effect. The results then support a granule-associated K+ transport in pancreatic acinar cells and suggest that it is ATP and lysophospholipid sensitive.

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Zúñiga, Leandro, Angel Cayo, Wendy González, Cristian Vilos, and Rafael Zúñiga. "Potassium Channels as a Target for Cancer Therapy: Current Perspectives." OncoTargets and Therapy Volume 15 (July 2022): 783–97. http://dx.doi.org/10.2147/ott.s326614.

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41

Bielanska, J., J. Hernandez-Losa, M. Perez-Verdaguer, T. Moline, R. Somoza, S. Cajal, E. Condom, J. Ferreres, and A. Felipe. "Voltage-Dependent Potassium Channels Kv1.3 and Kv1.5 in Human Cancer." Current Cancer Drug Targets 9, no. 8 (December 1, 2009): 904–14. http://dx.doi.org/10.2174/156800909790192400.

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Hernandez-Resendiz, Ileana, Franziska Hartung, and Luis A. Pardo. "Antibodies Targeting KV Potassium Channels: A Promising Treatment for Cancer." Bioelectricity 1, no. 3 (September 1, 2019): 180–87. http://dx.doi.org/10.1089/bioe.2019.0022.

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Bielanska, Joanna, Javier Hernandez-Losa, Mireia Perez-Verdaguer, Teresa Moline, Rosa Somoza, Santiago Ramon y Cajal, Enric Condom, Joan Carles Ferreres, and Antonio Felipe. "Voltage-Dependent Potassium Channels Kv1.3 and Kv1.5 in Human Cancer." Biophysical Journal 102, no. 3 (January 2012): 135a. http://dx.doi.org/10.1016/j.bpj.2011.11.746.

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44

Rustenbeck, I., C. Dickel, C. Herrmann, and T. Grimmsmann. "Mitochondria Present in Excised Patches From Pancreatic B-cells May Form Microcompartments With ATP-Dependent Potassium Channels." Bioscience Reports 19, no. 2 (April 1, 1999): 89–98. http://dx.doi.org/10.1023/a:1020106409700.

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Experiments with inside-out patches excised from pancreatic B-cells have yielded evidence that mitochondria are often contained in the cytoplasmic plug protruding into the tip of patch pipette. When intact B-cells were loaded with the fluorescent mitochondrial stain, rhodamine 123, and membrane patches excised from these cells, a green fluorescence could be observed in the lumen at the tip of the patch pipette. The same result was obtained with the mitochondrial stain, MitoTracker Green FM, which is only fluorescent in a membrane-bound state. Furthermore, the open probability of ATP-dependent potassium (KATP) channels in inside-out patches was influenced by mitochondrial fuels and inhibitors. Respiratory substrates like tetramethyl phenylene diamine (2 mM) plus ascorbate (5 mM) or α-ketoisocaproic acid (10 mM) reduced the open probability of KATP channels in inside-out patches significantly (down to 57% or 65% of control, respectively). This effect was antagonized by the inhibitor of cytochrome oxidase, sodium azide (5 mM). Likewise, the inhibitor of succinate dehydrogenase, malonate (5 mM), increased the open probability of KATP channels in the presence of succinate (1 mM). However, oligomycin in combination with antimycin and rotenone did not increase open probability. Although it cannot be excluded that these effects result from a direct interaction with the KATP channels, the presence of mitochondria in the close vicinity permits the hypothesis that changes in mitochondrial metabolism are involved, mitochondria and KATP channels thus forming functional microcompartments.

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López-Vera, Estuardo, Luis Martínez-Hernández, Manuel B. Aguilar, Elisa Carrillo, and Joanna Gajewiak. "Studies of Conorfamide-Sr3 on Human Voltage-Gated Kv1 Potassium Channel Subtypes." Marine Drugs 18, no. 8 (August 13, 2020): 425. http://dx.doi.org/10.3390/md18080425.

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Recently, Conorfamide-Sr3 (CNF-Sr3) was isolated from the venom of Conus spurius and was demonstrated to have an inhibitory concentration-dependent effect on the Shaker K+ channel. The voltage-gated potassium channels play critical functions on cellular signaling, from the regeneration of action potentials in neurons to the regulation of insulin secretion in pancreatic cells, among others. In mammals, there are at least 40 genes encoding voltage-gated K+ channels and the process of expression of some of them may include alternative splicing. Given the enormous variety of these channels and the proven use of conotoxins as tools to distinguish different ligand- and voltage-gated ion channels, in this work, we explored the possible effect of CNF-Sr3 on four human voltage-gated K+ channel subtypes homologous to the Shaker channel. CNF-Sr3 showed a 10 times higher affinity for the Kv1.6 subtype with respect to Kv1.3 (IC50 = 2.7 and 24 μM, respectively) and no significant effect on Kv1.4 and Kv1.5 at 10 µM. Thus, CNF-Sr3 might become a novel molecular probe to study diverse aspects of human Kv1.3 and Kv1.6 channels.

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Boyle, Yasmin, Terrance G. Johns, and Emily V. Fletcher. "Potassium Ion Channels in Malignant Central Nervous System Cancers." Cancers 14, no. 19 (September 29, 2022): 4767. http://dx.doi.org/10.3390/cancers14194767.

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Malignant central nervous system (CNS) cancers are among the most difficult to treat, with low rates of survival and a high likelihood of recurrence. This is primarily due to their location within the CNS, hindering adequate drug delivery and tumour access via surgery. Furthermore, CNS cancer cells are highly plastic, an adaptive property that enables them to bypass targeted treatment strategies and develop drug resistance. Potassium ion channels have long been implicated in the progression of many cancers due to their integral role in several hallmarks of the disease. Here, we will explore this relationship further, with a focus on malignant CNS cancers, including high-grade glioma (HGG). HGG is the most lethal form of primary brain tumour in adults, with the majority of patient mortality attributed to drug-resistant secondary tumours. Hence, targeting proteins that are integral to cellular plasticity could reduce tumour recurrence, improving survival. This review summarises the role of potassium ion channels in malignant CNS cancers, specifically how they contribute to proliferation, invasion, metastasis, angiogenesis, and plasticity. We will also explore how specific modulation of these proteins may provide a novel way to overcome drug resistance and improve patient outcomes.

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Mao, Xia, Yongping Chai, and Yu-Fung Lin. "Dual regulation of the ATP-sensitive potassium channel by caffeine." American Journal of Physiology-Cell Physiology 292, no. 6 (June 2007): C2239—C2258. http://dx.doi.org/10.1152/ajpcell.00326.2006.

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ATP-sensitive potassium (KATP) channels couple cellular metabolic status to changes in membrane electrical properties. Caffeine (1,2,7-trimethylxanthine) has been shown to inhibit several ion channels; however, how caffeine regulates KATP channels was not well understood. By performing single-channel recordings in the cell-attached configuration, we found that bath application of caffeine significantly enhanced the currents of Kir6.2/SUR1 channels, a neuronal/pancreatic KATP channel isoform, expressed in transfected human embryonic kidney (HEK)293 cells in a concentration-dependent manner. Application of nonselective and selective phosphodiesterase (PDE) inhibitors led to significant enhancement of Kir6.2/SUR1 channel currents. Moreover, the stimulatory action of caffeine was significantly attenuated by KT5823, a specific PKG inhibitor, and, to a weaker extent, by BAPTA/AM, a membrane-permeable Ca2+ chelator, but not by H-89, a selective PKA inhibitor. Furthermore, the stimulatory effect was completely abrogated when KT5823 and BAPTA/AM were co-applied with caffeine. In contrast, the activity of Kir6.2/SUR1 channels was decreased rather than increased by caffeine in cell-free inside-out patches, while tetrameric Kir6.2LRKR368/369/370/371AAAA channels were suppressed regardless of patch configurations. Caffeine also enhanced the single-channel currents of recombinant Kir6.2/SUR2B channels, a nonvascular smooth muscle KATP channel isoform, although the increase was smaller. Moreover, bidirectional effects of caffeine were reproduced on the KATP channel present in the Cambridge rat insulinoma G1 (CRI-G1) cell line. Taken together, our data suggest that caffeine exerts dual regulation on the function of KATP channels: an inhibitory regulation that acts directly on Kir6.2 or some closely associated regulatory protein(s), and a sulfonylurea receptor (SUR)-dependent stimulatory regulation that requires cGMP-PKG and intracellular Ca2+-dependent signaling.

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Wu, Jing-Xiang, Dian Ding, Mengmeng Wang, Yunlu Kang, Xin Zeng, and Lei Chen. "Ligand binding and conformational changes of SUR1 subunit in pancreatic ATP-sensitive potassium channels." Protein & Cell 9, no. 6 (March 28, 2018): 553–67. http://dx.doi.org/10.1007/s13238-018-0530-y.

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Zhao, Yu-Feng, Jianming Pei, and Chen Chen. "Activation of ATP-sensitive potassium channels in rat pancreatic β-cells by linoleic acid through both intracellular metabolites and membrane receptor signalling pathway." Journal of Endocrinology 198, no. 3 (June 11, 2008): 533–40. http://dx.doi.org/10.1677/joe-08-0105.

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ATP-sensitive potassium channels (KATP channels) determine the excitability of pancreatic β-cells and importantly regulate glucose-stimulated insulin secretion (GSIS). Long-chain free fatty acids (FFAs) decrease GSIS after long-term exposure to β-cells, but the effects of exogenous FFAs on KATP channels are not yet well clarified. In this study, the effects of linoleic acid (LA) on membrane potential (MP) and KATP channels were observed in primary cultured rat pancreatic β-cells. LA (20 μM) induced hyperpolarization of MP and opening of KATP channels, which was totally reversed and inhibited by tolbutamide, a KATP channel blocker. Inhibition of LA metabolism by acyl-CoA synthetase inhibitor, triacsin C (10 μM), partially inhibited LA-induced opening of KATP channels by 64%. The non-FFA G protein-coupled receptor (GPR) 40 agonist, GW9508 (40 μM), induced an opening of KATP channels, which was similar to that induced by LA under triacsin C treatment. Blockade of protein kinases A and C did not influence the opening of KATP channels induced by LA and GW9508, indicating that these two protein kinase pathways are not involved in the action of LA on KATP channels. The present study demonstrates that LA induces hyperpolarization of MP by activating KATP channels via both intracellular metabolites and activation of GPR40. It indicates that not only intracellular metabolites of FFAs but also GPR40-mediated pathways take part in the inhibition of GSIS and β-cell dysfunction induced by FFAs.

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Yan, Fei-Fei, Emily B. Pratt, Pei-Chun Chen, Fang Wang, William R. Skach, Larry L. David, and Show-Ling Shyng. "Role of Hsp90 in Biogenesis of the β-Cell ATP-sensitive Potassium Channel Complex." Molecular Biology of the Cell 21, no. 12 (June 15, 2010): 1945–54. http://dx.doi.org/10.1091/mbc.e10-02-0116.

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The pancreatic β-cell ATP-sensitive potassium (KATP) channel is a multimeric protein complex composed of four inwardly rectifying potassium channel (Kir6.2) and four sulfonylurea receptor 1 (SUR1) subunits. KATP channels play a key role in glucose-stimulated insulin secretion by linking glucose metabolism to membrane excitability. Many SUR1 and Kir6.2 mutations reduce channel function by disrupting channel biogenesis and processing, resulting in insulin secretion disease. To better understand the mechanisms governing KATP channel biogenesis, a proteomics approach was used to identify chaperone proteins associated with KATP channels. We report that chaperone proteins heat-shock protein (Hsp)90, heat-shock cognate protein (Hsc)70, and Hsp40 are associated with β-cell KATP channels. Pharmacologic inhibition of Hsp90 function by geldanamycin reduces, whereas overexpression of Hsp90 increases surface expression of wild-type KATP channels. Coimmunoprecipitation data indicate that channel association with the Hsp90 complex is mediated through SUR1. Accordingly, manipulation of Hsp90 protein expression or function has significant effects on the biogenesis efficiency of SUR1, but not Kir6.2, expressed alone. Interestingly, overexpression of Hsp90 selectively improved surface expression of mutant channels harboring a subset of disease-causing SUR1 processing mutations. Our study demonstrates that Hsp90 regulates biogenesis efficiency of heteromeric KATP channels via SUR1, thereby affecting functional expression of the channel in β-cell membrane.

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Journal articles on the topic 'Potassium channels, pancreatic cancer'

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