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Lysosomal Ion Channels and Human Diseases
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Peng Huang, Mengnan Xu, Yi Wu, Xian-Ping Dong
Interestingly, the BK channel is recently reported to be highly expressed in the lysosomal membrane (Cao et al., 2015b; Wang et al., 2017). The lysosomal localization of the BK channel is determined by two dileucine motifs, D(485)ACLI and D(731)PLLI, located in the RCK domain in the large cytoplasmic C-terminus (Cao et al., 2015b). In agreement with what was known for BK channel on the PM, an increase in the cytosolic Ca2+ concentration dramatically increases BK currents and shifts the voltage dependence of channel activation to more negative potentials (Cao et al., 2015b; Wang et al., 2017). This shift of voltage dependence makes BK easily activated in response to a local Ca2+ increase upon the opening of lysosomal Ca2+ release channels (Berkefeld et al., 2010; Fakler and Adelman, 2008; Salkoff et al., 2006). Like the BK channel in the PM, the lysosomal BK channel is inhibited by paxilline, quinidine, clofilium and iberiotoxin (Garrity et al., 2016; Wang et al., 2017) but activated by NS1619 (Bentzen et al., 2014; Olesen et al., 1994) and isopimaric acid (Garrity et al., 2016; Wang et al., 2017; Yamamura et al., 2001). These data indicate that the BK channel in lysosomes functions in the same manner as its PM counterpart.
The role of lysosomal ion channels in lysosome dysfunction
Published in Inhalation Toxicology, 2021
Rebekah L. Kendall, Andrij Holian
Through its interactions with TRPML1, the BK channel plays a role in both lysosomal trafficking and acidification. Inhibiting BK activity with the selective BK-blocker paxilline can be countered by upregulation of TRPML1 activity, suggesting that BK acts in coordination withTRPML1 to regulate lysosomal functions such as lysosomal membrane trafficking (Cao et al. 2015). Additionally, BK inhibition suppresses lysosomal Ca2+ release and causes Ca2+ accumulation in lysosomes, which can also be rescued by cotreatment with the TRPML1 activator, ML-SA1 (Cao et al. 2015), suggesting a regulatory role of the BK channel in Ca2+ flux. BK deficiency results in dysfunctional lysosome storage and a similar phenotype to LSDs, mucolipidosis type IV and Niemann-Pick (Cao et al. 2015). In contrast, overexpression of BK rescues impaired cholesterol trafficking in NPC1−/− cells, and is necessary for TRPML1 activity to enhance lysosomal exocytosis (Cao et al. 2015). In fact, because of its role in lysosomal storage, Zhong et al. explored the BK channel as a therapeutic target for LSDs. They found that BK activation with varying agonists resulted in rescue of lysosomal storage and exocytosis in several LSDs (Zhong et al. 2016). This suggests the BK channel as a potential therapeutic target in any number of diseases marked by dysfunctional lysosomal exocytosis or reduced TRPML1 activity.
Antitumor Effect of Bryonia dioïca Methanol Extract: In Vitro and In Vivo Study
Published in Nutrition and Cancer, 2020
Imen Ben Abdessamad, Ines Bouhlel, Leila Chekir-Ghedira, Mounira Krifa
Moreover, we analyzed the organ index in lung weight of mice from different batches. The results obtained are encouraging us to do a histological examination of the lungs, which are considered a site of metastatic melanoma (15). We found that mice without M extract treatment have metastatic pulmonary colonies which are absent in the treated ones. These results contribute to disclosing the mechanism. FAK could participate in the migration and invasion of cancer cells. Several studies indicate that FAK expression is intensively correlated with malignant or metastatic disease (26) and the inhibition effect of FAK leads to apoptosis (27, 28). The western blot analysis reveals that M50 inhibits FAK, Src, and paxilline in its total or active form. Src and ERK1/2 are reduced in mice treated with M extract. It is well-known that ERK1/2 is involved in the gene transcription by activating nuclear proteins. The deregulated expression of this protein induces apoptosis (17). To further confirm our results, we examined the apoptotic effect of M extract in vivo extracts through nuclear labeling with acridine orange (condensed chromatin).
BK channels and a cGMP-dependent protein kinase (PKG) function through independent mechanisms to regulate the tolerance of synaptic transmission to acute oxidative stress at the Drosophila larval neuromuscular junction
Published in Journal of Neurogenetics, 2018
Wesley L. Bollinger, Nadia Sial, Ken Dawson-Scully
A previous study assessed the protective effect of BK channel blockade in a human neuronal cell line SH-SY5Y during H2O2-induced oxidative stress and CoCl2-induced hypoxia mimetic insults; the results revealed that specific BK channel activators, isopimaric acid and NS1619, exacerbated cytotoxicity, whereas inhibition of BK channels using TEA and tetrandrine provided a neuroprotective effect (Zhang, 2016). Because increases in [Ca2+]i activate BK channels, K+ channel blockers may be utilized in protecting neurons from oxidative stress. The findings from Zhang (2016) are consistent with our results, demonstrating that inhibition of BK channel and voltage-gated K+ channel conductance protects synaptic transmission during acute oxidative stress. Further confirming the role of BK channel inhibition in neuroprotection, a recent study provided evidence of BK channel inhibitors, including iberiotoxin, charybdotoxin, paxilline, and TEA, protecting neurons from stroke-induced insults (Chen et al., 2013). Consequently, the results from Chen et al. (2013) indicate that optimizing the dosage range of specific BK channel blockers (iberiotoxin) and K+ channel inhibitors (TEA) may assist in the development of effective treatments for stroke-induced cell death.