scholarly journals Effectiveness in Block by Dexmedetomidine of Hyperpolarization-Activated Cation Current, Independent of Its Agonistic Effect on α2-Adrenergic Receptors

2020 ◽  
Vol 21 (23) ◽  
pp. 9110
Author(s):  
Te-Ling Lu ◽  
Te-Jung Lu ◽  
Sheng-Nan Wu
Keyword(s):  
Adrenergic Receptors ◽  
Time Course ◽  
Ionic Currents ◽  
Inhibitory Effect ◽  
Firing Frequency ◽  
Neuroendocrine Cells ◽  
Gh3 Cells ◽  
Membrane Excitability ◽  
Cation Current

Dexmedetomidine (DEX), a highly selective agonist of α2-adrenergic receptors, has been tailored for sedation without risk of respiratory depression. Our hypothesis is that DEX produces any direct perturbations on ionic currents (e.g., hyperpolarization-activated cation current, Ih). In this study, addition of DEX to pituitary GH3 cells caused a time- and concentration-dependent reduction in the amplitude of Ih with an IC50 value of 1.21 μM and a KD value of 1.97 μM. A hyperpolarizing shift in the activation curve of Ih by 10 mV was observed in the presence of DEX. The voltage-dependent hysteresis of Ih elicited by long-lasting triangular ramp pulse was also dose-dependently reduced during its presence. In continued presence of DEX (1 μM), further addition of OXAL (10 μM) or replacement with high K+ could reverse DEX-mediated inhibition of Ih, while subsequent addition of yohimbine (10 μM) did not attenuate the inhibitory effect on Ih amplitude. The addition of 3 μM DEX mildly suppressed the amplitude of erg-mediated K+ current. Under current-clamp potential recordings, the exposure to DEX could diminish the firing frequency of spontaneous action potentials. In pheochromocytoma PC12 cells, DEX was effective at suppressing Ih together with a slowing in activation time course of the current. Taken together, findings from this study strongly suggest that during cell exposure to DEX used at clinically relevant concentrations, the DEX-mediated block of Ih appears to be direct and would particularly be one of the ionic mechanisms underlying reduced membrane excitability in the in vivo endocrine or neuroendocrine cells.

scholarly journals Evidence for Effective Inhibitory Actions on Hyperpolarization-Activated Cation Current Caused by Ganoderma Triterpenoids, the Main Active Constitutents of Ganoderma Spores

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4256 ◽  
Author(s):  
Wei-Ting Chang ◽  
Zi-Han Gao ◽  
Yi-Ching Lo ◽  
Sheng-Nan Wu
Keyword(s):  
Ionic Currents ◽  
Inhibitory Effect ◽  
Firing Frequency ◽  
Gh3 Cells ◽  
Heart Cells ◽  
Excitable Cells ◽  
Cell Current ◽  
Spontaneous Action

The triterpenoid fraction of Ganoderma (Ganoderma triterpenoids, GTs) has been increasingly demonstrated to provide effective antioxidant, neuroprotective or cardioprotective activities. However, whether GTs is capable of perturbing the transmembrane ionic currents existing in electrically excitable cells is not thoroughly investigated. In this study, an attempt was made to study whether GTs could modify hyperpolarization-activated cation currents (Ih) in pituitary tumor (GH3) cells and in HL-1 atrial cardiomyocytes. In whole-cell current recordings, the addition of GTs produced a dose-dependent reduction in the amplitude of Ih in GH3 cells with an IC50 value of 11.7 µg/mL, in combination with a lengthening in activation time constant of the current. GTs (10 µg/mL) also caused a conceivable shift in the steady-state activation curve of Ih along the voltage axis to a more negative potential by approximately 11 mV. Subsequent addition of neither 8-cyclopentyl-1,3-dipropylxanthine nor 8-(p-sulfophenyl)theophylline, still in the presence of GTs, could attenuate GTs-mediated inhibition of Ih. In current-clamp voltage recordings, GTs diminished the firing frequency of spontaneous action potentials in GH3 cells, and it also decreased the amplitude of sag potential in response to hyperpolarizing current stimuli. In murine HL-1 cardiomyocytes, the GTs addition also suppressed the amplitude of Ih effectively. In DPCPX (1 µM)-treated HL-1 cells, the inhibitory effect of GTs on Ih remained efficacious. Collectively, the inhibition of Ih caused by GTs is independent of its possible binding to adenosine receptors and it might have profound influence in electrical behaviors of different types of electrically excitable cells (e.g., pituitary and heart cells) if similar in vitro or in vivo findings occur.

scholarly journals Synergistic Inhibition of Delayed Rectifier K+ and Voltage-Gated Na+ Currents by Artemisinin in Pituitary Tumor (GH3) Cells

2017 ◽  
Vol 41 (5) ◽  
pp. 2053-2066 ◽  
Author(s):  
Edmund Cheung So ◽  
Sheng-Nan Wu ◽  
Ping-Ching Wu ◽  
Hui-Zhen  Chen ◽  
Chia-Jung Yang
Keyword(s):  
Pituitary Tumor ◽  
Ionic Currents ◽  
Neuroendocrine Cells ◽  
Endocrine Function ◽  
Gh3 Cells ◽  
Delayed Rectifier ◽  
Membrane Excitability ◽  
Inactivation Curve ◽  
Voltage Gated

Background: Artemisinin (ART) is an anti-malarial agent reported to influence endocrine function. Methods: Effects of ART on ionic currents and action potentials (APs) in pituitary tumor (GH3) cells were evaluated by patch clamp techniques. Results: ART inhibited the amplitude of delayed-rectifier K+ current (IK(DR)) in response to membrane depolarization and accelerated the process of current inactivation. It exerted an inhibitory effect on IK(DR) with an IC50 value of 11.2 µM and enhanced IK(DR) inactivation with a KD value of 14.7 µM. The steady-state inactivation curve of IK(DR) was shifted to hyperpolarization by 10 mV. Pretreatment of chlorotoxin (1 µM) or iloprost (100 nM) did not alter the magnitude of ART-induced inhibition of IK(DR) in GH3 cells. ART also decreased the peak amplitude of voltage-gated Na+ current (INa) with a concentration-dependent slowing in inactivation rate. Application of KMUP-1, an inhibitor of late INa, was effective at reversing ART-induced prolongation in inactivation time constant of INa. Under current-clamp recordings, ART alone reduced the amplitude of APs and prolonged the duration of APs. Conclusion: Under ART exposure, the inhibitory actions on both IK(DR) and INa could be a potential mechanisms through which this drug influences membrane excitability of endocrine or neuroendocrine cells appearing in vivo.

scholarly journals Characterization of Inhibitory Effectiveness in Hyperpolarization-Activated Cation Currents by a Group of ent-Kaurane-Type Diterpenoids from Croton tonkinensis

2020 ◽  
Vol 21 (4) ◽  
pp. 1268 ◽  
Author(s):  
Ping-Chung Kuo ◽  
Yen-Chin Liu ◽  
Yi-Ching Lo ◽  
Sheng-Nan Wu
Keyword(s):  
Ionic Currents ◽  
Neuroendocrine Cells ◽  
Flowering Plant ◽  
Gh3 Cells ◽  
Functional Activities ◽  
Cation Current ◽  
Voltage Dependent ◽  
K Current ◽  
The Common

Croton is an extensive flowering plant genus in the spurge family, Euphorbiaceae. Three croton compounds with the common ent-kaurane skeleton have been purified from Croton tonkinensis. Methods: We examined any modifications of croton components (i.e., croton-01 [ent-18-acetoxy-7α-hydroxykaur-16-en-15-one], croton-02 [ent-7α,14β-dihydroxykaur-16-en-15-one] and croton-03 [ent-1β-acetoxy-7α,14β-dihydroxykaur-16-en-15-one] on either hyperpolarization-activated cation current (Ih) or erg-mediated K+ current identified in pituitary tumor (GH3) cells and in rat insulin-secreting (INS-1) cells via patch-clamp methods. Results: Addition of croton-01, croton-02, or croton-03 effectively and differentially depressed Ih amplitude. Croton-03 (3 μM) shifted the activation curve of Ih to a more negative potential by approximately 11 mV. The voltage-dependent hysteresis of Ih was also diminished by croton-03 administration. Croton-03-induced depression of Ih could not be attenuated by SQ-22536 (10 μM), an inhibitor of adenylate cyclase, but indeed reversed by oxaliplatin (10 μM). The Ih in INS-1 cells was also depressed effectively by croton-03. Conclusion: Our study highlights the evidence that these ent-kaurane diterpenoids might conceivably perturb these ionic currents through which they have high influence on the functional activities of endocrine or neuroendocrine cells.

scholarly journals Characterization of the Synergistic Inhibition of IK(erg) and IK(DR) by Ribociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor

2020 ◽  
Vol 21 (21) ◽  
pp. 8078
Author(s):  
Pin-Yen Liu ◽  
Wei-Ting Chang ◽  
Sheng-Nan Wu
Keyword(s):  
Pituitary Tumor ◽  
Time Course ◽  
Transforming Growth Factor ◽  
Ionic Currents ◽  
Transforming Growth Factor Β ◽  
Gh3 Cells ◽  
Delayed Rectifier ◽  
Cyclin Dependent Kinase ◽  
Cation Current ◽  
K Current

Ribociclib (RIB, LE011, Kisqali®), an orally administered inhibitor of cyclin-dependent kinase-4/6 (CDK-4/6) complex, is clinically effective for the treatment of several malignancies, including advanced breast cancer. However, information regarding the effects of RIB on membrane ion currents is limited. In this study, the addition of RIB to pituitary tumor (GH3) cells decreased the peak amplitude of erg-mediated K+ current (IK(erg)), which was accompanied by a slowed deactivation rate of the current. The IC50 value for RIB-perturbed inhibition of deactivating IK(erg) in these cells was 2.7 μM. In continued presence of μM RIB, neither the subsequent addition of 17β-estradiol (30 μM), phorbol 12-myristate 13-acetate (10 μM), or transforming growth factor-β (1 μM) counteracted the inhibition of deactivating IK(erg). Its presence affected the decrease in the degree of voltage-dependent hysteresis for IK(erg) elicitation by long-duration triangular ramp voltage commands. The presence of RIB differentially inhibited the peak or sustained component of delayed rectifier K+ current (IK(DR)) with an effective IC50 of 28.7 or 11.4 μM, respectively, while it concentration-dependently decreased the amplitude of M-type K+ current with IC50 of 13.3 μM. Upon 10-s long membrane depolarization, RIB elicited a decrease in the IK(DR) amplitude, which was concomitant with an accelerated inactivation time course. However, the inability of RIB (10 μM) to modify the magnitude of the hyperpolarization-activated cation current was disclosed. The mean current–voltage relationship of IK(erg) present in HL-1 atrial cardiomyocytes was inhibited in the presence of RIB (10 μM). Collectively, the hyperpolarization-activated cation current was observed. RIB-mediated perturbations in ionic currents presented herein are upstream of its suppressive action on cytosolic CDK-4/6 activities and partly participates in its modulatory effects on the functional activities of pituitary tumor cells (e.g., GH3 cells) or cardiac myocytes (e.g., HL-1 cells).

scholarly journals Evidence for the Capability of Roxadustat (FG-4592), an Oral HIF Prolyl-Hydroxylase Inhibitor, to Perturb Membrane Ionic Currents: An Unidentified yet Important Action

2019 ◽  
Vol 20 (23) ◽  
pp. 6027 ◽  
Author(s):  
Wei-Ting Chang ◽  
Yi-Ching Lo ◽  
Zi-Han Gao ◽  
Sheng-Nan Wu
Keyword(s):  
Time Course ◽  
Hypoxia Inducible Factor ◽  
Ionic Currents ◽  
Membrane Depolarization ◽  
Prolyl Hydroxylase ◽  
Gh3 Cells ◽  
Heart Cells ◽  
Patch Clamp Technique ◽  
Hif Prolyl Hydroxylase

Roxadustat (FG-4592), an analog of 2-oxoglutarate, is an orally-administered, heterocyclic small molecule known to be an inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase. However, none of the studies have thus far thoroughly investigated its possible perturbations on membrane ion currents in endocrine or heart cells. In our studies, the whole-cell current recordings of the patch-clamp technique showed that the presence of roxadustat effectively and differentially suppressed the peak and late components of IK(DR) amplitude in response to membrane depolarization in pituitary tumor (GH3) cells with an IC50 value of 5.71 and 1.32 μM, respectively. The current inactivation of IK(DR) elicited by 10-sec membrane depolarization became raised in the presence of roxadustatt. When cells were exposed to either CoCl2 or deferoxamine (DFO), the IK(DR) elicited by membrane depolarization was not modified; however, nonactin, a K+-selective ionophore, in continued presence of roxadustat, attenuated roxadustat-mediated inhibition of the amplitude. The steady-state inactivation of IK(DR) could be constructed in the presence of roxadustat. Recovery of IK(DR) block by roxadustat (3 and 10 μM) could be fitted by a single exponential with 382 and 523 msec, respectively. The roxadustat addition slightly suppressed erg-mediated K+ or hyperpolarization-activated cation currents. This drug also decreased the peak amplitude of voltage-gated Na+ current with a slowing in inactivation rate of the current. Likewise, in H9c2 heart-derived cells, the addition of roxadustat suppressed IK(DR) amplitude in combination with the shortening in inactivation time course of the current. In high glucose-treated H9c2 cells, roxadustat-mediated inhibition of IK(DR) remained unchanged. Collectively, despite its suppression of HIF prolyl hydroxylase, inhibitory actions of roxadustat on different types of ionic currents possibly in a non-genomic fashion might provide another yet unidentified mechanism through which cellular functions are seriously perturbed, if similar findings occur in vivo.

scholarly journals Effective Activation by Kynurenic Acid and Its Aminoalkylated Derivatives on M-Type K+ Current

2021 ◽  
Vol 22 (3) ◽  
pp. 1300
Author(s):  
Yi-Ching Lo ◽  
Chih-Lung Lin ◽  
Wei-Yu Fang ◽  
Bálint Lőrinczi ◽  
István Szatmári ◽  
...  
Keyword(s):  
Kynurenic Acid ◽  
Time Course ◽  
Ionic Currents ◽  
Gh3 Cells ◽  
Excitable Cells ◽  
Patch Clamp Technique ◽  
Open Probability ◽  
Type K ◽  
K Current

Kynurenic acid (KYNA, 4-oxoquinoline-2-carboxylic acid), an intermediate of the tryptophan metabolism, has been recognized to exert different neuroactive actions; however, the need of how it or its aminoalkylated amide derivative N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-oxo-1,4-dihydroquinoline-2-carboxamide (KYNA-A4) exerts any effects on ion currents in excitable cells remains largely unmet. In this study, the investigations of how KYNA and other structurally similar KYNA derivatives have any adjustments on different ionic currents in pituitary GH3 cells and hippocampal mHippoE-14 neurons were performed by patch-clamp technique. KYNA or KYNA-A4 increased the amplitude of M-type K+ current (IK(M)) and concomitantly enhanced the activation time course of the current. The EC50 value required for KYNA- or KYNA-A4 -stimulated IK(M) was yielded to be 18.1 or 6.4 μM, respectively. The presence of KYNA or KYNA-A4 shifted the relationship of normalized IK(M)-conductance versus membrane potential to more depolarized potential with no change in the gating charge of the current. The voltage-dependent hysteretic area of IK(M) elicited by long-lasting triangular ramp pulse was observed in GH3 cells and that was increased during exposure to KYNA or KYNA-A4. In cell-attached current recordings, addition of KYNA raised the open probability of M-type K+ channels, along with increased mean open time of the channel. Cell exposure to KYNA or KYNA-A4 mildly inhibited delayed-rectifying K+ current; however, neither erg-mediated K+ current, hyperpolarization-activated cation current, nor voltage-gated Na+ current in GH3 cells was changed by KYNA or KYNA-A4. Under whole-cell, current-clamp recordings, exposure to KYNA or KYNA-A4 diminished the frequency of spontaneous action potentials; moreover, their reduction in firing frequency was attenuated by linopirdine, yet not by iberiotoxin or apamin. In hippocampal mHippoE-14 neurons, the addition of KYNA also increased the IK(M) amplitude effectively. Taken together, the actions presented herein would be one of the noticeable mechanisms through which they modulate functional activities of excitable cells occurring in vivo.

scholarly journals Effective Perturbations on the Amplitude and Hysteresis of Erg-Mediated Potassium Current Caused by 1-Octylnonyl 8-[(2-hydroxyethyl)[6-oxo-6(undecyloxy)hexyl]amino]-octanoate (SM-102), a Cationic Lipid

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1367
Author(s):  
Hsin-Yen Cho ◽  
Tzu-Hsien Chuang ◽  
Sheng-Nan Wu
Keyword(s):  
Endocrine Cells ◽  
Time Course ◽  
Cationic Lipid ◽  
Ionic Currents ◽  
Gh3 Cells ◽  
Bath Application ◽  
Bv2 Cells ◽  
Rat Pituitary ◽  
K Current

SM-102 (1-octylnonyl 8-[(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino]-octanoate) is an amino cationic lipid that has been tailored for the formation of lipid nanoparticles and it is one of the essential ingredients present in the ModernaTM COVID-19 vaccine. However, to what extent it may modify varying types of plasmalemmal ionic currents remains largely uncertain. In this study, we investigate the effects of SM-102 on ionic currents either in two types of endocrine cells (e.g., rat pituitary tumor (GH3) cells and mouse Leydig tumor (MA-10) cells) or in microglial (BV2) cells. Hyperpolarization-activated K+ currents in these cells bathed in high-K+, Ca2+-free extracellular solution were examined to assess the effects of SM-102 on the amplitude and hysteresis of the erg-mediated K+ current (IK(erg)). The SM-102 addition was effective at blocking IK(erg) in a concentration-dependent fashion with a half-maximal concentration (IC50) of 108 μM, a value which is similar to the KD value (i.e., 134 μM) required for its accentuation of deactivation time constant of the current. The hysteretic strength of IK(erg) in response to the long-lasting isosceles-triangular ramp pulse was effectively decreased in the presence of SM-102. Cell exposure to TurboFectinTM 8.0 (0.1%, v/v), a transfection reagent, was able to inhibit hyperpolarization-activated IK(erg) effectively with an increase in the deactivation time course of the current. Additionally, in GH3 cells dialyzed with spermine (30 μM), the IK(erg) amplitude progressively decreased; moreover, a further bath application of SM-102 (100 μM) or TurboFectin (0.1%) diminished the current magnitude further. In MA-10 Leydig cells, the IK(erg) was also blocked by the presence of SM-102 or TurboFectin. The IC50 value for SM-102-induced inhibition of IK(erg) in MA-10 cells was 98 μM. In BV2 microglial cells, the amplitude of the inwardly rectifying K+ current was inhibited by SM-102. Taken together, the presence of SM-102 concentration-dependently inhibited IK(erg) in endocrine cells (e.g., GH3 or MA-10 cells), and such action may contribute to their functional activities, assuming that similar in vivo findings exist.

scholarly journals Characterization in Dual Activation by Oxaliplatin, a Platinum-Based Chemotherapeutic Agent of Hyperpolarization-Activated Cation and Electroporation-Induced Currents

2020 ◽  
Vol 21 (2) ◽  
pp. 396 ◽  
Author(s):  
Wei-Ting Chang ◽  
Zi-Han Gao ◽  
Shih-Wei Li ◽  
Ping-Yen Liu ◽  
Yi-Ching Lo ◽  
...  
Keyword(s):  
Ionic Currents ◽  
Gh3 Cells ◽  
Dependent Manner ◽  
Induced Current ◽  
Membrane Excitability ◽  
Concentration Dependent Manner ◽  
Term Administration ◽  
Inward Currents ◽  
Dual Activation

Oxaliplatin (OXAL) is regarded as a platinum-based anti-neoplastic agent. However, its perturbations on membrane ionic currents in neurons and neuroendocrine or endocrine cells are largely unclear, though peripheral neuropathy has been noted during its long-term administration. In this study, we investigated how the presence of OXAL and other related compounds can interact with two types of inward currents; namely, hyperpolarization-activated cation current (Ih) and membrane electroporation-induced current (IMEP). OXAL increased the amplitude or activation rate constant of Ih in a concentration-dependent manner with effective EC50 or KD values of 3.2 or 6.4 μM, respectively, in pituitary GH3 cells. The stimulation by this agent of Ih could be attenuated by subsequent addition of ivabradine, protopine, or dexmedetomidine. Cell exposure to OXAL (3 μM) resulted in an approximately 11 mV rightward shift in Ih activation along the voltage axis with minimal changes in the gating charge of the curve. The exposure to OXAL also effected an elevation in area of the voltage-dependent hysteresis elicited by long-lasting triangular ramp. Additionally, its application resulted in an increase in the amplitude of IMEP elicited by large hyperpolarization in GH3 cells with an EC50 value of 1.3 μM. However, in the continued presence of OXAL, further addition of ivabradine, protopine, or dexmedetomidine always resulted in failure to attenuate the OXAL-induced increase of IMEP amplitude effectively. Averaged current-voltage relation of membrane electroporation-induced current (IMEP) was altered in the presence of OXAL. In pituitary R1220 cells, OXAL-stimulated Ih remained effective. In Rolf B1.T olfactory sensory neurons, this agent was also observed to increase IMEP in a concentration-dependent manner. In light of the findings from this study, OXAL-mediated increases of Ih and IMEP may coincide and then synergistically act to increase the amplitude of inward currents, raising the membrane excitability of electrically excitable cells, if similar in vivo findings occur.

Mitochondrial Ca2+ Activates a Cation Current in Aplysia Bag Cell Neurons

2010 ◽  
Vol 103 (3) ◽  
pp. 1543-1556 ◽  
Author(s):  
Charlene M. Hickey ◽  
Julia E. Geiger ◽  
Chris J. Groten ◽  
Neil S. Magoski
Keyword(s):  
Endoplasmic Reticulum ◽  
Ion Channels ◽  
Time Course ◽  
Reversal Potential ◽  
Neuroendocrine Cells ◽  
Dependent Manner ◽  
Inward Current ◽  
Cation Current ◽  
Intracellular Ca ◽  
Bag Cell Neurons

Ion channels may be gated by Ca2+ entering from the extracellular space or released from intracellular stores—typically the endoplasmic reticulum. The present study examines how Ca2+ impacts ion channels in the bag cell neurons of Aplysia californica. These neuroendocrine cells trigger ovulation through an afterdischarge involving Ca2+ influx from Ca2+ channels and Ca2+ release from both the mitochondria and endoplasmic reticulum. Liberating mitochondrial Ca2+ with the protonophore, carbonyl cyanide-4-trifluoromethoxyphenyl-hydrazone (FCCP), depolarized bag cell neurons, whereas depleting endoplasmic reticulum Ca2+ with the Ca2+-ATPase inhibitor, cyclopiazonic acid, did not. In a concentration-dependent manner, FCCP elicited an inward current associated with an increase in conductance and a linear current/voltage relationship that reversed near −40 mV. The reversal potential was unaffected by changing intracellular Cl−, but left-shifted when extracellular Ca2+ was removed and right-shifted when intracellular K+ was decreased. Strong buffering of intracellular Ca2+ decreased the current, although the response was not altered by blocking Ca2+-dependent proteases. Furthermore, fura imaging demonstrated that FCCP elevated intracellular Ca2+ with a time course similar to the current itself. Inhibiting either the V-type H+-ATPase or the ATP synthetase failed to produce a current, ruling out acidic Ca2+ stores or disruption of ATP production as mechanisms for the FCCP response. Similarly, any involvement of reactive oxygen species potentially produced by mitochondrial depolarization was mitigated by the fact that dialysis with xanthine/xanthine oxidase did not evoke an inward current. However, both the FCCP-induced current and Ca2+ elevation were diminished by disabling the mitochondrial permeability transition pore with the alkylating agent, N-ethylmaleimide. The data suggest that mitochondrial Ca2+ gates a voltage-independent, nonselective cation current with the potential to drive the afterdischarge and contribute to reproduction. Employing Ca2+ from mitochondria, rather than the more common endoplasmic reticulum, represents a diversification of the mechanisms that influence neuronal activity.

scholarly journals Curcumin Sensitizes Prolactinoma to Bromocriptine by Activating the ERK/EGR1 and Inhibiting AKT/GSK3β Signaling Pathway

2021 ◽  
Author(s):  
Chao Tang ◽  
Junhao Zhu ◽  
Feng Yuan ◽  
Jin Yang ◽  
Xiangming Cai ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Expression Profiles ◽  
Inhibitory Effect ◽  
Gh3 Cells ◽  
Growth Inhibitory Effect ◽  
Growth Inhibitory ◽  
The Difference

Abstract Although bromocriptine (BRC) as first-line drugs are recommended for treating patients with prolactinoma, a minority of patients with prolactinoma resistance to BRC. Moreover, our previous study showed that the difference in drug sensitivity in BRC- treated rat prolactinoma cells, MMQ cells are more resistant to BRC, and GH3 cells are more sensitive to BRC. Curcumin (Cur) has been shown to inhibit proliferation of prolactinoma cell lines. The aim of this study is to further investigate whether Cur could enhance the growth-inhibitory effect of BRC resistance on prolactinoma cell lines and its possible mechanism. CCK-8 kit was used to test cell growth. Cell-cycle analysis and apoptosis was performed by flow cytometry. Electron microscopy was used to test autophagosome. The mRNA expression profiles were analysed using the Affymetrix Gene-Chip array. Western blotting was used to test protein expression. Our data showed that Cur enhanced the growth-inhibitory effect of BRC on GH3 and MMQ cell proliferation. BRC and Cur both induced cell apoptosis, and Cur could significantly increase the apoptosis of BRC on pituitary adenoma cells through the ERK/EGR1 signaling pathway. Moreover, Cur could enhance the autophagic cell death (ACD) of BRC on tumor cell by inhibiting the AKT/GSK3β signaling pathway. The same results were confirmed in vivo study. Taken together, Cur sensitizes rat pituitary adenoma cell to BRC by activating the ERK/EGR1 and inhibiting AKT/GSK3β signaling pathway.

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