• The Korean Journal of Physiology and Pharmacology
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• 제15권5호
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• pp.279-283
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• 2011

Quercetin (3,3',4',5,7-pentahydroxyflavone) is an attractive therapeutic flavonoid for cancer treatment because of its beneficial properties including apoptotic, antioxidant, and antiproliferative effects on cancer cells. However, the exact mechanism of action of quercetin on ion channel modulation is poorly understood in bladder cancer 253J cells. In this study, we demonstrated that large conductance $Ca^{2+}$-activated $K^+$ ($BK_{Ca}$) or MaxiK channels were functionally expressed in 253J cells, and quercetin increased $BK_{Ca}$ current in a concentration dependent and reversible manner using a whole cell patch configuration. The half maximal activation concentration ($IC_{50}$) of quercetin was $45.5{\pm}7.2{\mu}m$. The quercetin-evoked $BK_{Ca}$ current was inhibited by tetraethylammonium (TEA; 5 mM) a non-specific $BK_{Ca}$ blocker and iberiotoxin (IBX; 100 nM) a $BK_{Ca}$-specific blocker. Quercetin-induced membrane hyperpolarization was measured by fluorescence-activated cell sorting (FACS) with voltage sensitive dye, bis (1,3-dibutylbarbituric acid) trimethine oxonol ($DiBAC_4$2(3); 100 nM). Quercetin-evoked hyperpolarization was prevented by TEA. Quercetin produced an antiproliferative effect ($30.3{\pm}13.5%$) which was recovered to $53.3{\pm}10.5%$ and $72.9{\pm}3.7%$ by TEA and IBX, respectively. Taken together our results indicate that activation of $BK_{Ca}$ channels may be considered an important target related to the action of quercetin on human bladder cancer cells.

• The Korean Journal of Physiology and Pharmacology
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• 제21권2호
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• pp.259-265
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• 2017

Excessive influx and the subsequent rapid cytosolic elevation of $Ca^{2+}$ in neurons is the major cause to induce hyperexcitability and irreversible cell damage although it is an essential ion for cellular signalings. Therefore, most neurons exhibit several cellular mechanisms to homeostatically regulate cytosolic $Ca^{2+}$ level in normal as well as pathological conditions. Delayed rectifier $K^+$ channels ($I_{DR}$ channels) play a role to suppress membrane excitability by inducing $K^+$ outflow in various conditions, indicating their potential role in preventing pathogenic conditions and cell damage under $Ca^{2+}$-mediated excitotoxic conditions. In the present study, we electrophysiologically evaluated the response of $I_{DR}$ channels to hyperexcitable conditions induced by high $Ca^{2+}$ pretreatment (3.6 mM, for 24 hours) in cultured hippocampal neurons. In results, high $Ca^{2+}$-treatment significantly increased the amplitude of $I_{DR}$ without changes of gating kinetics. Nimodipine but not APV blocked $Ca^{2+}$-induced $I_{DR}$ enhancement, confirming that the change of $I_{DR}$ might be targeted by $Ca^{2+}$ influx through voltage-dependent $Ca^{2+}$ channels (VDCCs) rather than NMDA receptors (NMDARs). The VDCC-mediated $I_{DR}$ enhancement was not affected by either $Ca^{2+}$-induced $Ca^{2+}$ release (CICR) or small conductance $Ca^{2+}$-activated $K^+$ channels (SK channels). Furthermore, PP2 but not H89 completely abolished $I_{DR}$ enhancement under high $Ca^{2+}$ condition, indicating that the activation of Src family tyrosine kinases (SFKs) is required for $Ca^{2+}$-mediated $I_{DR}$ enhancement. Thus, SFKs may be sensitive to excessive $Ca^{2+}$ influx through VDCCs and enhance $I_{DR}$ to activate a neuroprotective mechanism against $Ca^{2+}$-mediated hyperexcitability in neurons.