nox4 Recent studies show that the expression and
Recent studies show that the expression and function of some ion channels such as voltage-gated potassium channels, sodium channels and calcium channels are closely related to the proliferation, migration, and invasion of tumor cells , , . Firstly, the expression of ion channels is changed frequently in human cancers. Secondly, the dysfunction of ion channels will seriously affect the physiological function of cancerous cells in tumor progression, such as the growth speed, the cellular signal transduction and invasiveness of the tumor cells. Thirdly, ion channels represent one of the few pharmaceutically tractable molecular classes . Compared with other proteins, the main advantage of ion channel is the accessibility from the extracellular side as an effective modulator. The importance of K+ and Cl− channels is maintaining dynamic changes for cell shape and volume, which is essential to increase the ability to movement and invasion. The inhibition of these channels damaged the invasion and migration of cancer cells, finally restricting the malignant transformation and tumor progression in several tumor system . Thus, these findings suggest that ion channels may be a potential target for diagnosis, treatment, and prognosis in tumor therapy. However, there are still difficulties and challenges in the ion channels for the targeted treatment. Ion channel is still a new research field in oncology; most channels have no tumor specific of expressing ubiquitously in different tissues and cells. So, the application of ion channels as molecular targeted drugs for cancer treatment remains major challenge . At last, there\'s a great need for designing even more useful and specific channel inhibitors employing various methods.
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Introduction Chloride-conducting members of the cysteine loop ligand-gated ion channel (cys-loop LGIC) family play an important role in inhibitory synaptic transmission in the nervous systems of vertebrates and invertebrates. γ-aminobutyric nox4 (GABA)-gated chloride channels (GABACls) are extensively expressed in the nervous systems of arthropods and nematodes as well as in higher animals (Buckingham et al., 2005). In contrast, cys-loop glutamate-gated chloride channels (GluCls) are found only in invertebrates (Cull-Candy, 1976; Wolstenholme, 2010). GABACls and GluCls are molecular targets for macrocyclic lactone insecticides (avermectins), which can activate these receptors directly, potentiate the response to the binding of their respective neurotransmitter or antagonize the agonist-induced channel current (Fuse et al., 2016; Wolstenholme, 2012). Phenylpyrazoles (e.g. fipronil) mainly target GABA receptors (Buckingham et al., 2005), but fipronil also showed inhibitory effects on GluCls, which acts as a blocker of these two types of LGICs (Kita et al., 2014; Narahashi et al., 2010; Wu et al., 2017; Zhao et al., 2004). Cys-loop LGICs assemble as pentamers and each subunit has four transmembrane segments (TM1-TM4), a large N-terminal section that forms the extracellular neurotransmitter-binding domain and a comparatively smaller intracellular domain comprised mainly of the TM3-TM4 linker. LGICs can form as homomers or heteromers and different subunit combinations can produce receptors with diverse structural, functional and pharmacological properties. Six genes encode GluCl subunits in the nematode Caenorhabditis elegans and mite Tetranychus urticae (Jones and Sattelle, 2008; Dermauw et al., 2012). In contrast, GluCls in insect species are encoded by a single gene. Studies on several species of Diptera, Hymenoptera, Coleoptera, Hemiptera show that subunit diversity arises from posttranscriptional alternations of mRNA i.e. from splice variants and RNA editing (Furutani et al., 2014; Jones et al., 2010; Jones and Sattelle, 2006; Kita et al., 2014; Meyers et al., 2015; Semenov and Pak, 1999; Wang et al., 2016a; Wu et al., 2017). An invertebrate GluCl gene consists typically of 10 exons (Fig. 1A) and an overview of the five different processes that produce different subunit variants is shown in Fig. 1B. In particular, exons 3 and 9 have been identified as “hot spot” domains of alternative splicing (Fig. 1B).