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In rat pancreatic -cells, glyburide has an inhibitory effect on the Kv currents in a concentration-dependent manner, acting synergistically with its blockage of K ATP channels to facilitate therapeutic efficacy ( The delayed-rectifier Kv1.3 channels serve as a potential modulator in immune response, due to its regulation in electrical activity of immune cells such as T lymphocytes ( Besides cardiomyocytes and neural cells, the hERG channel (Kv11.1) encoded by human ether-a-go-go -related gene, which is associated with long-QT syndrome type 2 (LQT2), also is expressed in pancreatic and cells, participating in the secretion of glucagon and insulin, respectively ( 2.2 Na + channels Expression of voltage-gated Na + channels (VGSCs) is available in human pancreatic -cells, with predominant levels for Na V 1.6 and the remainder being Na V 1.7, Na V 1.3 and Na V 1.2, which appears to account for large TTX-sensitive Na + currents and be responsible for the upstroke of the action potential ( Interestingly, human pancreatic glandule and pancreatic islet -cells express the epithelial sodium channel alpha subunit (-ENaC) ( 2.3 TRP channels Several types of transient receptor potential (TRP) channels, including TRPC1, TRPM2, TRPM3, TRPM4, TRPM7, TRPP1, TRPML1, and TRPML3, have been identified in human -cells ( 2+ oscillations in pancreatic islets, and accordingly is a positive regulator of glucose-induced insulin release ( 2+ from intracellular stores is mediated through TRPM2, which is activated by intracellular ADPR in a lysosomal compartment ( High levels of TRPA1 channels are detectable in rodent pancreatic -cells, and exposure to agonists of TRPA1 results in Ca 2+ influx and induce the basal insulin release, suggestive of promotion of insulin secretion via the depolarization arising from both activation of TRPA1 and inhibition of K ATP channels ( 2.4 Cl channels Accumulating evidence unveils that volume-regulated anion channels (VRAC or SWELL1), cystic fibrosis transmembrane conductance regulator (CFTR) and Ca 2+ -activated Cl channels (CaCCs) are involved in regulating the insulin secretion, possibly via Cl efflux-mediated membrane depolarization ( Like K ATP channels, CFTR Cl channel, a member of the adenosine triphosphate (ATP) binding cassette (ABC) superfamily, is regulated by intracellular ATP with a cAMP/PKA-dependent feature ( ATP channels composed of Kir6 and SUR subunits, both of which share several properties in their sulfonylurea binding sites ( 3 Indirect modulation: the suppression of sulfonylurea-mediated activation of Epac2A on diverse ion channels Adenosine 3,5,-monophosphate (cAMP), an important second messenger, has been well established as a key regulator for the insulin release during the glucose stimuli, which is mediated via PKA-dependent manner and PKA-independent manner (as known as Epac2A way) ( Previous studies uncovered that many sulfonylureas such as tolbutamide and glibenclamide, but not gliclazide, directly enabled the activation of Epac2A/Rap1 signaling in pancreatic -cells, indicating an additional way of promoting insulin secretion, with exception of directly inhibiting K ATP channels ( 2+ ( Interestingly, several K + channels are also targeted by Epac, showing that possibly there is an indirect regulatory approach in which the impact of sulfonylureas on K + channels arises from direct activation of Epac by these chemicals
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