Search Results (3)

GAL-021 has recently been developed as a novel breathing control modulator. However, modifications of ionic currents produced by this agent remain uncertain, although its efficacy in suppressing the activity of big-conductance Ca²⁺-activated K⁺ (BK_Ca) channels has been reported. In pituitary tumor (GH₃) cells, we found that the presence of GAL-021 decreased the amplitude of macroscopic Ca²⁺-activated K⁺ current (I_K(Ca)) in a concentration-dependent manner with an effective IC₅₀ of 2.33 μM. GAL-021-mediated reduction of I_K(Ca) was reversed by subsequent application of verteporfin or ionomycin; however, it was not by that of diazoxide. In inside-out current recordings, the addition of GAL-021 to the bath markedly decreased the open-state probability of BK_Ca channels. This agent also resulted in a rightward shift in voltage dependence of the activation curve of BK_Ca channels; however, neither the gating charge of the curve nor single-channel conductance of the channel was changed. There was an evident lengthening of the mean closed time of BK_Ca channels in the presence of GAL-021, with no change in mean open time. The GAL-021 addition also suppressed M-type K⁺ current with an effective IC₅₀ of 3.75 μM; however, its presence did not alter the amplitude of erg-mediated K⁺ current, or mildly suppressed delayed-rectifier K⁺ current. GAL-021 at a concentration of 30 μM could also suppress hyperpolarization-activated cationic current. In HEK293T cells expressing α-hSlo, the addition of GAL-021 was also able to suppress the BK_Ca-channel open probabilities, and GAL-021-mediated suppression of BK_Ca-channel activity was attenuated by further addition of BMS-191011. Collectively, the GAL-021 effects presented herein do not exclusively act on BK_Ca channels and these modifications on ionic currents exert significant influence on the functional activities of electrically excitable cells occurring in vivo. Full article

Several tumor entities have been reported to overexpress K_Ca3.1 potassium channels due to epigenetic, transcriptional, or post-translational modifications. By modulating membrane potential, cell volume, or Ca²⁺ signaling, K_Ca3.1 has been proposed to exert pivotal oncogenic functions in tumorigenesis, malignant progression, metastasis, and therapy resistance. Moreover, K_Ca3.1 is expressed by tumor-promoting stroma cells such as fibroblasts and the tumor vasculature suggesting a role of K_Ca3.1 in the adaptation of the tumor microenvironment. Combined, this features K_Ca3.1 as a candidate target for innovative anti-cancer therapy. However, immune cells also express K_Ca3.1 thereby contributing to T cell activation. Thus, any strategy targeting K_Ca3.1 in anti-cancer therapy may also modulate anti-tumor immune activity and/or immunosuppression. The present review article highlights the potential of K_Ca3.1 as an anti-tumor target providing an overview of the current knowledge on its function in tumor pathogenesis with emphasis on vasculo- and angiogenesis as well as anti-cancer immune responses. Full article

Type II vestibular hair cells (VHCs II) contain big-conductance Ca²⁺-dependent K⁺ channels (BK) and L-type calcium channels. Our previous studies in guinea pig VHCs II indicated that acetylcholine (ACh) evoked the BK current by triggering the influx of Ca²⁺ ions through l-type Ca²⁺ channels, which was mediated by M2 muscarinic ACh receptor (mAChRs). Aminoglycoside antibiotics, such as gentamicin (GM), are known to have vestibulotoxicity, including damaging effects on the efferent nerve endings on VHCs II. This study used the whole-cell patch clamp technique to determine whether GM affects the vestibular efferent system at postsynaptic M2-mAChRs or the membrane ion channels. We found that GM could block the ACh-induced BK current and that inhibition was reversible, voltage-independent, and dose-dependent with an IC₅₀ value of 36.3 ± 7.8 µM. Increasing the ACh concentration had little influence on GM blocking effect, but increasing the extracellular Ca²⁺ concentration ([Ca²⁺]_o) could antagonize it. Moreover, 50 µM GM potently blocked Ca²⁺ currents activated by (-)-Bay-K8644, but did not block BK currents induced by NS1619. These observations indicate that GM most likely blocks the M2 mAChR-mediated response by competing with Ca²⁺ at the l-type calcium channel. These results provide insights into the vestibulotoxicity of aminoglycoside antibiotics on mammalian VHCs II. Full article