Carbamazepine promotes surface expression of mutant Kir6.2-A28V ATP-sensitive potassium channels by modulating Golgi retention and autophagy

Lin, Ching‐Han; Lin, Yu Chi; Yang, Sheng‐Ming; Chen, Pei–Chun

doi:10.1016/j.jbc.2022.101904

Cited by 4 publications

(5 citation statements)

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“…For example, in the control period (i.e., CBZ was not present), the peak and sustained components of I K(erg) at the level of −100 mV were 780 ± 53 and 112 ± 34 pA, respectively (n = 7), while cell exposure to 100 μM CBZ significantly decreased peak and sustained I K(erg) to 568 ± 48 and 58 ± 20 pA, respectively (n = 7; t value = 3.2; p < 0.05). Moreover, as cells were continually exposed to 100 μM CBZ, a further application of 30 μM diazoxide [ 30 , 62 ], an activator of ATP-sensitive K + channels, was unable to reverse CBZ-induced inhibition of I K(erg) . Therefore, the addition of CBZ could result in a mild inhibition of I K(erg) in response to long-lasting membrane hyperpolarization.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we found that CBZ could slightly inhibit I K(erg) in response to long-lasting membrane hyperpolarization in Neuro-2a cells. Earlier investigations have demonstrated the capability of CBZ to decrease the activity of ATP-sensitive K + channels [ 29 , 30 ]. However, during whole-cell configuration made under our experimental conditions, the ATP concentration of the pipette internal solution was 3 mM, a value that adequately blocks most K ATP -channel activity.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, in continued presence of CBZ, further addition of diazoxide failed to attenuate CBZ-mediated inhibition of I K(erg) . Diazoxide is an opener of K ATP channels [ 30 , 62 ]. It, therefore, seems unlikely that the inhibitory effect of CBZ on I K(erg) magnitude seen in Neuro-2a cells is mainly due to its activity as a regulator of K ATP channels.…”

Section: Discussionmentioning

confidence: 99%

“…Of additional notice, although CBZ is safe and effective in anti-convulsant activities, the unwanted events following CBZ treatment, such as hyponatremia, QT-interval prolongation, hyperprolactinemia, change in pitch perception and idiosyncratic reactions, have gradually emerged [ 5 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. The effectiveness of CBZ in inhibiting the activity of ATP-sensitive K + (K ATP ) channels has also been demonstrated [ 29 , 30 ]. However, this drug was reported to restore neuronal signaling, protein synthesis, and cognitive function in a mouse model of fragile X syndrome [ 31 ] as well as to improve motor impairment either in myotonia congenita or in the model of Machado-Joseph disease [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Characterization in Inhibitory Effectiveness of Carbamazepine in Voltage-Gated Na+ and Erg-Mediated K+ Currents in a Mouse Neural Crest-Derived (Neuro-2a) Cell Line

Cho

Chiang

et al. 2022

IJMS

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Carbamazepine (CBZ, Tegretol®) is an anticonvulsant used in the treatment of epilepsy and neuropathic pain; however, several unwanted effects of this drug have been noticed. Therefore, the regulatory actions of CBZ on ionic currents in electrically excitable cells need to be reappraised, although its efficacy in suppressing voltage-gated Na+ current (INa) has been disclosed. This study was undertaken to explore the modifications produced by CBZ on ionic currents (e.g., INa and erg-mediated K+ current [IK(erg)]) measured from Neuro-2a (N2a) cells. In these cells, we found that this drug differentially suppressed the peak (transient, INa(T)) and sustained (late, INa(L)) components of INa in a concentration-dependent manner with effective IC50 of 56 and 18 μM, respectively. The overall current–voltage relationship of INa(T) with or without the addition of CBZ remained unchanged; however, the strength (i.e., ∆area) in the window component of INa (INa(W)) evoked by the short ascending ramp pulse (Vramp) was overly lessened in the CBZ presence. Tefluthrin (Tef), a synthetic pyrethroid, known to stimulate INa, augmented the strength of the voltage-dependent hysteresis (Hys(V)) of persistent INa (INa(P)) in response to the isosceles-triangular Vramp; moreover, further application of CBZ attenuated Tef-mediated accentuation of INa(P)’s Hys(V). With a two-step voltage protocol, the recovery of INa(T) inactivation seen in Neuro-2a cells became progressively slowed by adding CBZ; however, the cumulative inhibition of INa(T) evoked by pulse train stimulation was enhanced during exposure to this drug. Neuro-2a-cell exposure to CBZ (100 μM), the magnitude of erg-mediated K+ current measured throughout the entire voltage-clamp steps applied was mildly inhibited. The docking results regarding the interaction of CBZ and voltage-gate Na+ (NaV) channel predicted the ability of CBZ to bind to some amino-acid residues in NaV due to the existence of a hydrogen bond or hydrophobic contact. It is conceivable from the current investigations that the INa (INa(T), INa(L), INa(W), and INa(P)) residing in Neuro-2a cells are susceptible to being suppressed by CBZ, and that its block on INa(L) is larger than that on INa(T). Collectively, the magnitude and gating of NaV channels produced by the CBZ presence might have an impact on its anticonvulsant and analgesic effects occurring in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization in Inhibitory Effectiveness of Carbamazepine in Voltage-Gated Na+ and Erg-Mediated K+ Currents in a Mouse Neural Crest-Derived (Neuro-2a) Cell Line

Cho

Chiang

et al. 2022

IJMS

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“…Human Kir6.2 (hKir6.2), and SUR1 (hSUR1) (Origene, Rockville, MD, USA) were cloned into the pcDNA3 plasmid as described previously ( 23 , 24 ). Site-directed mutagenesis was performed using Phusion Flash high-fidelity DNA polymerase (Thermo Fisher Scientific, Waltham, MA, USA), and the mutations were verified by sequencing.…”

Section: Methodsmentioning

confidence: 99%

Genotype-phenotype correlation in Taiwanese children with diazoxide-unresponsive congenital hyperinsulinism

Lee,

Tsai,

Chang

et al. 2023

Front. Endocrinol.

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ObjectiveCongenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study was to elucidate genetic etiologies of Taiwanese children with the most severe diazoxide-unresponsive CHI and analyze their genotype-phenotype correlations.MethodsWe combined Sanger with whole exome sequencing (WES) to analyze CHI-related genes. The allele frequency of the most common variant was estimated by single-nucleotide polymorphism haplotype analysis. The functional effects of the ATP-sensitive potassium (KATP) channel variants were assessed using patch clamp recording and Western blot.ResultsNine of 13 (69%) patients with ten different pathogenic variants (7 in ABCC8, 2 in KCNJ11 and 1 in GCK) were identified by the combined sequencing. The variant ABCC8 p.T1042QfsX75 identified in three probands was located in a specific haplotype. Functional study revealed the human SUR1 (hSUR1)-L366F KATP channels failed to respond to intracellular MgADP and diazoxide while hSUR1-R797Q and hSUR1-R1393C KATP channels were defective in trafficking. One patient had a de novo dominant mutation in the GCK gene (p.I211F), and WES revealed mosaicism of this variant from another patient.ConclusionPathogenic variants in KATP channels are the most common underlying cause of diazoxide-unresponsive CHI in the Taiwanese cohort. The p.T1042QfsX75 variant in the ABCC8 gene is highly suggestive of a founder effect. The I211F mutation in the GCK gene and three rare SUR1 variants associated with defective gating (p.L366F) or traffic (p.R797Q and p.R1393C) KATP channels are also associated with the diazoxide-unresponsive phenotype.

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The cellular pathways that maintain the quality control and transport of diverse potassium channels

Nguyen

Brodsky

2023

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Carbamazepine promotes surface expression of mutant Kir6.2-A28V ATP-sensitive potassium channels by modulating Golgi retention and autophagy

Cited by 4 publications

References 45 publications

Characterization in Inhibitory Effectiveness of Carbamazepine in Voltage-Gated Na+ and Erg-Mediated K+ Currents in a Mouse Neural Crest-Derived (Neuro-2a) Cell Line

Characterization in Inhibitory Effectiveness of Carbamazepine in Voltage-Gated Na+ and Erg-Mediated K+ Currents in a Mouse Neural Crest-Derived (Neuro-2a) Cell Line

Genotype-phenotype correlation in Taiwanese children with diazoxide-unresponsive congenital hyperinsulinism

The cellular pathways that maintain the quality control and transport of diverse potassium channels

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