Ask about this productRelated genes to: KCNH6 antibody
- Gene:
- KCNH6 NIH gene
- Name:
- potassium voltage-gated channel subfamily H member 6
- Previous symbol:
- -
- Synonyms:
- Kv11.2, erg2, HERG2
- Chromosome:
- 17q23.3
- Locus Type:
- gene with protein product
- Date approved:
- 2002-07-10
- Date modifiied:
- 2016-02-04
Related products to: KCNH6 antibody
Related articles to: KCNH6 antibody
- Quinolines and artemisinins are the two most important antimalarial drugs worldwide. In addition to antimalarial effects, quinine has been extensively documented to directly stimulate insulin secretion, potentially causing hypoglycemia in malaria patients undergoing treatment through the inhibition of K channels, and artemisinins have been recently identified as small molecules that increase insulin secretion by functionally promoting the conversion of pancreatic α cells into β cells, which is promising for the therapy of diabetes. Here, to detect the precise function of these drugs in insulin secretion, glucose-stimulated insulin secretion (GSIS) test with isolated mouse islets and insulin secretion experiment in mice were performed. Quinine was the most potent insulin secretagogue of all three quinoline drugs tested in this study. Low-dose quinine potentiated insulin secretion in a high glucose-dependent manner through KCNH6 current inhibition rather than through classical K inhibition. However, artemisinins did not promote insulin secretion in vitro or in vivo. In particular, artemether significantly suppressed insulin secretion, decreased Ca influx and the expression levels of β-cell marker genes, contradicting the findings of previous studies suggesting that artemisinins promote the transformation of pancreatic α cells into β cells. Overall, our observations revealed the differential effects of two widely used antimalarial drugs, quinolines and artemisinins, on insulin secretion. Ascertaining the targets by which drugs affect insulin secretion may advance diabetes treatment. - Source: PubMed
Publication date: 2025/11/25
Lu JingXiong FengranZhang QianruiZhao RuxuanZhang ChenyangWei GangYang Jinkui - Fentanyl is widely used perioperatively and illicitly as a drug of abuse. As a potent μ-opioid receptor agonist, fentanyl canonically inhibits excitability through Gα intracellular signalling pathways resulting in analgesia and respiratory depression. However, fentanyl also paradoxically activates respiratory muscles causing a potentially lethal effect termed wooden chest syndrome. Here we show that fentanyl, but not morphine, causes a persistent tonic component of diaphragmatic muscle activity. Voltage-clamp studies reveal that fentanyl directly blocks a subset of ether-à-go-go-class potassium (K) channels. These channels are widely expressed in spinal motoneurons, including those innervating the diaphragm. A significant fraction of these motoneurons are excited by fentanyl, concomitant with blockade of K currents. Taken together we identified a novel off-target mechanism for fentanyl action, independent of μ-opioid receptor activation. Our findings may inform the design of safer analgesics and generalize beyond the activation of motoneurons to other neuronal circuits implicated in fentanyl-related maladaptive behaviours. KEY POINTS: High doses of fentanyl can cause a lethal phenotype termed 'wooden chest syndrome' (WCS) resulting from tonic contractions of respiratory-associated musculature, precluding the ability to mechanically inflate the lungs. In vivo murine diaphragmatic electromyograms reveal a tonic component of muscle activity elicited by fentanyl, but not morphine. Fentanyl reversibly blocks a subset of ether-à-go-go (EAG)-class potassium channels (EAG/Kv10 and ERG/Kv11 subclasses) expressed in HEK293 cells. Computational docking of fentanyl into cryogenic electron microscopy structures of these potassium channels predicts a binding site beneath the K selectivity filter. RT-PCR and RNA-scope in situ experiments reveal widespread expression of EAG/Kv10 (Kcnh1, Kcnh5) and ERG/Kv11 (Kcnh2, Kcnh6, Kcnh7) transcripts in cervical motoneurons, including phrenic motoneurons retrogradely labelled from the diaphragm. In vitro patch-clamp recordings from cervical spinal sections identifies a significant fraction of phrenic motoneurons (44%) electrically excited by fentanyl, concomitant with the blockade of a non-inactivating voltage-gated potassium current. Direct block of EAG potassium channels by fentanyl may contribute to WCS. - Source: PubMed
Publication date: 2025/10/19
Wei Aguan DBurgraff Nicholas JOliveira Luiz MMoreira Thiago SRamirez Jan-Marino - Mitochondrial glucose metabolism is critical for glucose-stimulated insulin secretion and glucose homeostasis in pancreatic β cells. We previously showed that KCNH6, a voltage-dependent potassium (Kv) channel, participated regulation of insulin secretion in pancreatic β cells, however, its role in mitochondrial metabolism remains unclear. Since we recently found that KCNH6 distributed in mitochondria, in this study, we investigated the role of KCNH6 in regulating mitochondrial function in pancreatic β cells by using a β cell-specific knockout (KCNH6-βKO) mouse model. Proteomics analysis of islets indicated that multiple proteins involved in mitochondrial metabolism were dysregulated in islets of KCNH6-βKO mice. Additionally, KCNH6-deficient β cells exhibited damaged mitochondria morphology and oxidative respiration dysfunction, which manifested as decreased glucose-induced ATP production, elevated NADH/NAD ratio and ROS levels. Impaired mitochondrial metabolism in βKO islets were significantly alleviated after the re-expression of KCNH6. Mechanistically, a physical interaction between KCNH6 and complex I assembly subunit Ndufa13 was detected, providing direct evidence of KCNH6's ability to regulate mitochondrial function. These results suggested that KCNH6 could be a promising therapeutic target for improving energy metabolism in β cells. - Source: PubMed
Han Xue-ChunLiu ChangJiang Ze-JuWang Zi-LuLi QiYuan Ying-ChaoWang HaoYang Jin-Kui - The Coptis chinensis (Franch) is widely used in diabetes therapies in traditional folk medicine from China, and we previously reported that its main active component, berberine (BBR), acted as an insulin secretagogue through blocking the KCNH6 potassium channel. However, the specific actions of BBR on insulin secretory granule (ISG) dynamics are largely unknown. Here, we analyzed the docking and fusion of ISGs from β-cells exposed to either short-term or long-term treatment with BBR. Under short-term treatment, at 8.3 mmol/L glucose, BBR slightly induced insulin secretion with a gradually increasing second phase only, showing an increased number of ISGs fused without stable docking to the plasma membrane. However, in the presence of 16.7 mmol/L glucose, biphasic insulin secretion by BBR was augmented significantly. The intracellular Ca level increased during the second phase by BBR, suggesting that the Ca dynamics contribute to the dynamics of insulin exocytosis. Under long-term BBR treatment for db/db mice, BBR restored impaired biphasic phases of insulin secretion by recovering the number of ISGs fused with or without predocking to the plasma membrane. In addition, BBR enhanced the docking capacity and increased biphasic Ca concentration after glucose stimulation. Further research revealed that the short-term treatment with BBR primarily promoted the fusion of ISGs through blocking KCNH6 channels, whereas the long-term treatment with BBR improved the docking and fusion of ISGs by an additional effect on activating the cAMP-PKA-CREB pathway. Hence, our study indicated that short-term and long-term treatment with BBR promoted insulin exocytosis through different mechanisms in pancreatic β cells. BBR could be a dual-action antidiabetic agent, acutely enhancing insulin secretion in response to glucose and chronically improving β-cell function in T2D. - Source: PubMed
Jiang Ze-JuLiu Yan-LiWang Zi-LuWang Hao - Insulin secretion is mainly regulated by two electrophysiological events, depolarization initiated by the closure of adenosine triphosphate (ATP)-sensitive K+ (KATP) channels and repolarization mediated by K+ efflux. Quinine, a natural component commonly used for the treatment of malaria, has been reported to directly stimulate insulin release and lead to hypoglycemia in patients during treatment through inhibiting KATP channels. In this study, we verified the insulinotropic effect of quinine on the isolated mouse pancreatic islets. We also revealed that low-dose quinine (<20 μM) did not directly provoke Ca2+ spikes or insulin secretion under low-glucose conditions but potentiated Ca2+ influx and insulin secretion induced by high glucose, which cannot be explained by KATP inhibition. KCNH6 (hERG2) is a voltage-dependent K+ (Kv) channel that plays a critical role in the repolarization of pancreatic β cells. Patch clamp experiments showed that quinine inhibited hERG channels at low micromolar concentrations. However, whether quinine can target KCNH6 to potentiate glucose-induced insulin secretion remains unclear. Here, we showed that in vivo administration of low-dose quinine (25 mg/kg) improved glucose tolerance and increased glucose-induced insulin release in wild-type control mice but not in Kcnh6-β-cell-specific knockout (βKO) mice. Consistently, in vitro treatment of primary islet β cells with low-dose quinine (10 μM) prolonged action potential duration and augmented glucose-induced Ca2+ influx in the wild-type control group but not in the Kcnh6-βKO group. Our results demonstrate that KCNH6 plays an important role in low-dose quinine-potentiated insulin secretion and provide new insights into KCNH6-targeted drug development. - Source: PubMed
Xiong Feng-RanZhu Juan-JuanZhu Xiao-RongLu JingYang Jin-Kui