Abstract:Abstract. Ranolazine, a piperazine derivative, is currently approved for the treatment of chronic angina. However, its ionic mechanisms in other types of cells remain unclear, although it is thought to be a selective blocker of late Na + current. This study was conducted to evaluate the possible effects of ranolazine on Na, and Ca
2+-activated K + current (I K(Ca) ) in pituitary tumor (GH 3 ) cells. Ranolazine depressed the transient and late components of I Na with different potencies. This drug exerted an in… Show more
“…1. Consistent with our previous observations in GH 3 cells (Liu and Wu 2003;Chen et al 2009;Huang et al 2011), hyperpolarizing voltage pulses induced an instantaneous current followed by a voltageand time-dependent elicitation of a K ? inward current, that is, a deactivating I K(erg) .…”
Section: Effect Of Dehp On I K(erg) In Gh 3 Cellssupporting
DEHP (bis(2-ethylhexyl)-phthalate) known to be an endocrine-disrupting chemical is a widely used phthalate. Little information regarding the effects of phthalate esters on ion currents is available. In this study, the effects of DEHP and other phthalate esters (DBEP: di(2-butoxyethyl)-phthalate and DMGP: di(2-methylglycol)-phthalate) on ion currents were investigated in pituitary GH₃ cells. Hyperpolarization-elicited K⁺ currents in GH3 cells bathed in high-K⁺, Ca²⁺-free solution were examined to evaluate the effects of DEHP, DBEP, and DMGP on the ether-a`-go-go-related-gene (erg) K⁺ current (IK(erg)). Addition of DEHP to GH₃ cells suppressed the amplitude of IK(erg) in a concentration-dependent manner with an IC₅₀ value of 16.3 μM. With a two-pulse protocol, addition of DEHP shifted the activation curve of IK(erg) to a depolarized potential by approximately 10 mV with no change in the rate of IK(erg) deactivation. This compound did not have any effects on delayed rectifier K⁺ current in GH₃ cells, while 4-aminopyridine-3-methanol (100 μM) suppressed this current significantly. DBEP (30 μM) had little or no effect on IK(erg), while DMGP (30 μM) slightly reduced it. In inside-out configuration, DEHP (30 μM) applied to the bath slightly reduced the activity of large-conductance Ca²⁺-activated K⁺ channels. DEHP (30 μM) increased the frequency of spontaneous action potentials (APs); however, this compound at the same concentration had no effect on AP firing in KCNH2 siRNA-transfected GH₃ cells. The effects described herein can contribute to their actions on functional activity of endocrine or neuroendocrine cells if similar results are found in vivo.
“…1. Consistent with our previous observations in GH 3 cells (Liu and Wu 2003;Chen et al 2009;Huang et al 2011), hyperpolarizing voltage pulses induced an instantaneous current followed by a voltageand time-dependent elicitation of a K ? inward current, that is, a deactivating I K(erg) .…”
Section: Effect Of Dehp On I K(erg) In Gh 3 Cellssupporting
DEHP (bis(2-ethylhexyl)-phthalate) known to be an endocrine-disrupting chemical is a widely used phthalate. Little information regarding the effects of phthalate esters on ion currents is available. In this study, the effects of DEHP and other phthalate esters (DBEP: di(2-butoxyethyl)-phthalate and DMGP: di(2-methylglycol)-phthalate) on ion currents were investigated in pituitary GH₃ cells. Hyperpolarization-elicited K⁺ currents in GH3 cells bathed in high-K⁺, Ca²⁺-free solution were examined to evaluate the effects of DEHP, DBEP, and DMGP on the ether-a`-go-go-related-gene (erg) K⁺ current (IK(erg)). Addition of DEHP to GH₃ cells suppressed the amplitude of IK(erg) in a concentration-dependent manner with an IC₅₀ value of 16.3 μM. With a two-pulse protocol, addition of DEHP shifted the activation curve of IK(erg) to a depolarized potential by approximately 10 mV with no change in the rate of IK(erg) deactivation. This compound did not have any effects on delayed rectifier K⁺ current in GH₃ cells, while 4-aminopyridine-3-methanol (100 μM) suppressed this current significantly. DBEP (30 μM) had little or no effect on IK(erg), while DMGP (30 μM) slightly reduced it. In inside-out configuration, DEHP (30 μM) applied to the bath slightly reduced the activity of large-conductance Ca²⁺-activated K⁺ channels. DEHP (30 μM) increased the frequency of spontaneous action potentials (APs); however, this compound at the same concentration had no effect on AP firing in KCNH2 siRNA-transfected GH₃ cells. The effects described herein can contribute to their actions on functional activity of endocrine or neuroendocrine cells if similar results are found in vivo.
“…6, there was no significant difference in the amplitude of I
Na between untreated cells (1.82 ± 0.3 nA, n = 8) and cells treated with SGX (10 μM) (1.81 ± 0.2 nA, n = 8, P > 0.05). However, in SGX-treated cells, addition of ranolazine (10 μM), a blocker of I
Na [27], was capable of suppressing the peak amplitude of I
Na significantly from 1.82 ± 0.2 nA to 0.98 ± 0.1 nA (n = 7, P < 0.05). Therefore, SGX treatment per se did not modify the amplitude of I
Na in these cells, while the presence of ranolazine remained effective at suppressing I
Na in SGX-treated cells.Fig.…”
BackgroundSugammadex (SGX) is a modified γ-cyclodextrin used for reversal of steroidal neuromuscular blocking agents during general anesthesia. Despite its application in clinical use, whether SGX treatment exerts any effects on membrane ion currents in neurons remains largely unclear. In this study, effects of SGX treatment on ion currents, particularly on delayed-rectifier K+ current [I
K(DR)], were extensively investigated in differentiated NSC-34 neuronal cells.ResultsAfter cells were exposed to SGX (30 μM), there was a reduction in the amplitude of I
K(DR) followed by an apparent slowing in current activation in response to membrane depolarization. The challenge of cells with SGX produced a depolarized shift by 15 mV in the activation curve of I
K(DR) accompanied by increased gating charge of this current. However, the inactivation curve of I
K(DR) remained unchanged following SGX treatment, as compared with that in untreated cells. According to a minimal reaction scheme, the lengthening of activation time constant of I
K(DR) caused by cell treatment with different SGX concentrations was quantitatively estimated with a dissociation constant of 17.5 μM, a value that is clinically achievable. Accumulative slowing in I
K(DR) activation elicited by repetitive stimuli was enhanced in SGX-treated cells. SGX treatment did not alter the amplitude of voltage-gated Na+ currents. In SGX-treated cells, dexamethasone (30 μM), a synthetic glucocorticoid, produced little or no effect on L-type Ca2+ currents, although it effectively suppressed the amplitude of this current in untreated cells.ConclusionsThe treatment of SGX may influence the amplitude and gating of I
K(DR) and its actions could potentially contribute to functional activities of motor neurons if similar results were found in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-016-0320-5) contains supplementary material, which is available to authorized users.
“…However, in our study, neither tetrodotoxin, ranolazine nor riluzole was demonstrated to have any effects on PALCAR-stimulated I MEP in GH 3 cells. Those compounds are recognized to suppress the amplitude of late Na + currents [32,33]. PALCAR produced a progressive increase of I MEP in GH 3 cells with an EC 50 value of 2.4 µM.…”
Background/Aims: The objective of this study is to examine the current signals in response to large hyperpolarizations with the aid of principal component analysis (PCA) to search for or even predict current fluctuations related to membrane electroporation-induced current (IMEP). Methods: The characteristics of principal eigenvalues generated for IMEP and the current signals at 10 sec prior to the start of initial IMEP (IPre) were examined. As membrane hyperpolarizations were applied at 0.1 Hz, the appearance of IMEP coincided with the higher principal eigenvalues extracted in PCA. Results: Subsequent addition of LaCl3 (100 µM) greatly reduced IMEP and associated principal eigenvalues. In real-time analysis for a single frame (i.e, 300 msec), in response to large hyperpolarization, multiple runs of heralded minuscule inward currents (Imin) occurring before large rise in current amplitudes were detected. With PCA, such heralded Imin was noted to coincide with the extreme principal eigenvalues. The duration of Imin together with large principal eigenvalues was influenced by different levels of membrane hyperpolarization. In GH3 cells, palmitoyl-L-carnitine (PALCAR), a long-chain acylcarnitine, effectively increased the IMEP amplitude with an EC50 value of 2.4 µM. However, in PALCAR-treated cells, the Imin together with higher principal eigenvalues disappeared, while in isoflurane-treated cells, Imin occurring before large rise of current amplitude remained intact. Similarly, the PCA analysis from IPre in RAW 264.6 macrophages showed the presence of herald Imin accompanied by the extreme principal eigenvalues. Conclusion: It is clear from this study that these large principal eigenvalues are representative of MEP-associated formation of electropores. Therefore, different compositions around the surface membrane of cells may alter the appearance of Imin followed by IMEP emergence.
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