Abstract
UCL-2077 (triphenylmethylaminomethyl)pyridine) was previously reported to suppress slow afterhyperpolarization in neurons. However, the information with respect to the effects of UCL-2077 on ionic currents is quite scarce. The addition of UCL-2077 decreased the amplitude of erg-mediated K+ current (IK(erg)) together with an increased deactivation rate of the current in pituitary GH3 cells. The IC50 and KD values of UCL-2077-induced inhibition of IK(erg) were 4.7 and 5.1 μM, respectively. UCL-2077 (10 μM) distinctly shifted the midpoint in the activation curve of IK(erg) to less hyperpolarizing potentials by 17 mV. Its presence decreased the degree of voltage hysteresis for IK(erg) elicitation by long-lasting triangular ramp pulse. It also diminished the probability of the opening of intermediate-conductance Ca2+-activated K+ channels. In cell-attached current recordings, UCL-2077 raised the frequency of action currents. When KCNH2 mRNA was knocked down, a UCL-2077-mediated increase in AC firing was attenuated. Collectively, the actions elaborated herein conceivably contribute to the perturbating effects of this compound on electrical behaviors of excitable cells.
Highlights
UCL-2077pyridine), which was discovered as a small-molecule blocker, has been reported to suppress the slow or late afterhyperpolarizations existing in different regions of either central neurons or brain slices [1,2,3,4,5,6,7,8]
Effect of UCL-2077 on the Frequency of Spontaneous Action Currents (ACs) In another set of recordings, we investigated whether UCL-2077 modulated the frequency of spontaneous ACs measured from GH3 cells
Another pertinent finding in this study is that, based on the estimation of changes in the za and zdeact values required for IK(erg) elicitation (Equations (4) And (5)), the addition of UCL-2077 significantly allowed those values to be smaller and the magnitude of its decrease in zdeact was greater than that in za
Summary
UCL-2077 (triphenylmethylaminomethyl)pyridine), which was discovered as a small-molecule blocker, has been reported to suppress the slow or late afterhyperpolarizations existing in different regions of either central neurons or brain slices [1,2,3,4,5,6,7,8]. The IK(erg) encoded by three different subfamilies of the gene KCNH is known to give rise to the pore-forming α-subunit of erg-mediated K+ (i.e., Kerg or KV11) channels [10], which is regarded to constitute the cloned counterpart of the rapidly activating delayed-rectifying K+ currents in heart cells These currents inherently existing in neurons or in different types of electrically excitable cell, such as endocrine or neuroendocrine cells, can highly influence the maintenance of the resting potential as well as the increase in subthreshold excitability [11,12], thereby leading to marked changes in the discharge rate of spontaneous action potentials (APs) [13,14,15,16]. Whether UCL-2077 produces any modifications in this type of ion channel is largely not explored, it has been demonstrated to suppress slow afterhyperpolarization [2,3,4,5,6,7,8]
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