Two-pore-domain potassium channels (K2P) family is widely expressed in many human cell types and organs, which has important regulatory effect on physiological processes. K2P is sensitive to a variety of chemical and physical stimuli, and they have also been critically implicated in transmission of neural signal, ion homeostasis, cell development and death, and synaptic plasticity. Aberrant expression and dysfunction of K2P channels are involved in a range of diseases, including autoimmune, central nervous system, cardiovascular disease and others. The scope of this review is to give a detailed overview of the structure, function, pharmacological regulation, and related diseases of TREK-1 channels, a member of the K2P family.
Potassium Channels, Tandem Pore Domain/genetics* ; Humans ; Animals ; Cardiovascular Diseases/physiopathology* ; Autoimmune Diseases/metabolism* ; Central Nervous System Diseases/physiopathology*

The family of voltage-gated potassium Kv2 channels consists of the Kv2.1 and Kv2.2 subtypes. Kv2.1 is constitutively highly phosphorylated in neurons and its function relies on its phosphorylation state. Whether the function of Kv2.2 is also dependent on its phosphorylation state remains unknown. Here, we investigated whether Kv2.2 channels can be phosphorylated by protein kinase C (PKC) and examined the effects of PKC-induced phosphorylation on their activity and function. Activation of PKC inhibited Kv2.2 currents and altered their steady-state activation in HEK293 cells. Point mutations and specific antibodies against phosphorylated S481 or S488 demonstrated the importance of these residues for the PKC-dependent modulation of Kv2.2. In layer II pyramidal neurons in cortical slices, activation of PKC similarly regulated native Kv2.2 channels and simultaneously reduced the frequency of action potentials. In conclusion, this study provides the first evidence to our knowledge that PKC-induced phosphorylation of the Kv2.2 channel controls the excitability of cortical pyramidal neurons.
Action Potentials ; HEK293 Cells ; Humans ; Protein Kinase C/metabolism* ; Pyramidal Cells/enzymology* ; Shab Potassium Channels/genetics*

OBJECTIVES: Epilepsy is a syndrome of central nervous system dysfunction caused by many reasons, which is mainly characterized by abnormal discharge of neurons in the brain. Therefore, finding new targets for epilepsy therapy has always been the focus and hotspot in neurological research field. Studies have found that 2-deoxy-D-glucose (2-DG) exerts anti-epileptic effect by up-regulation of K_ATP channel subunit Kir6.1, Kir6.2 mRNA and protein. By using the database of TargetScan and miRBase to perform complementary pairing analysis on the sequences of miRNA and related target genes, it predicted that miR-194 might be the upstream signaling molecule of K_ATP channel. This study aims to explore the mechanism by which 2-DG exerts its anti-epileptic effect by regulating K_ATP channel subunits Kir6.1 and Kir6.2 via miR-194. METHODS: A magnesium-free epilepsy model was established and randomly divided into a control group, an epilepsy group (EP group), an EP+2-DG group, and miR-194 groups (including EP+miR-194 mimic, EP+miR-194 mimic+2-DG, EP+miR-194 mimic control, EP+miR-194 inhibitor, EP+miR-194 inhibitor+2-DG, and EP+miR-194 inhibitor control groups). The 2-DG was used to intervene miR-194 mimics, patch-clamp method was used to detect the spontaneous recurrent epileptiform discharges, real-time PCR was used to detect neuronal miR-194, Kir6.1, and Kir6.2 expressions, and the protein levels of Kir6.1 and Kir6.2were detected by Western blotting. RESULTS: Compared with the control group, there was no significant difference in the amplitude of spontaneous discharge potential in the EP group (P>0.05), but the frequency of spontaneous discharge was increased (P<0.05). Compared with the EP group, the frequency of spontaneous discharge was decreased (P<0.05). Compared with the EP+miR-194 mimic control group, the mRNA and protein expressions of Kir6.1 and Kir6.2 in the EP+miR-194 mimic group were down-regulated (all P<0.05). Compared with the EP+miR-194 inhibitor control group, the mRNA and protein expressions of Kir6.1 and Kir6.2 in the EP+miR-194 inhibitor group were up-regulated (all P<0.05). After pretreatment with miR-194 mimics, the mRNA and protein expression levels of K_ATP channel subunits Kir6.1 and Kir6.2 were decreased (all P<0.05). Compared with the EP+2-DG group, the mRNA and protein expression levels of Kir6.1 and Kir6.2 in the EP+miR-194 mimic+2-DG group were down-regulated (all P<0.05) and the mRNA and protein expression levels of Kir6.1 and Kir6.2 in the EP+miR-194 inhibitor+2-DG group were up-regulated (all P<0.05). CONCLUSIONS The 2-DG might play an anti-epilepsy effect by up-regulating K_ATP channel subunits Kir6.1 and Kir6.2via miR-194.
Adenosine Triphosphate ; Anticonvulsants ; Deoxyglucose/pharmacology* ; Epilepsy/genetics* ; Glucose ; Humans ; MicroRNAs/genetics* ; Potassium Channels, Inwardly Rectifying/metabolism* ; RNA, Messenger/metabolism* ; Signal Transduction

Age-related hearing loss (AHL) is one of the most common sensory disorders among elderly persons. The inwardly rectifying potassium channel 5.1 (Kir5.1) plays a vital role in regulating cochlear K(+) circulation which is necessary for normal hearing. The distribution of Kir5.1 in C57BL/6J mice cochleae, and the relationship between the expression of Kir5.1 and the etiology of AHL were investigated. Forty C57BL/6J mice were randomly divided into four groups at 4, 12, 24 and 52 weeks of age respectively. The location of Kir5.1 was detected by immunofluorescence technique. The mRNA and protein expression of Kir5.1 was evaluated in mice cochleae using real-time polymerase-chain reactions (RT-PCR) and Western blotting respectively. Kir5.1 was detected in the type II and IV fibrocytes of the spiral ligament in the cochlear lateral wall of C57BL/6J mice. The expression levels of Kir5.1 mRNA and protein in the cochleae of aging C57BL/6J mice were down-regulated. It was suggested that the age-related decreased expression of Kir5.1 in the lateral wall of C57BL/6J mice was associated with hearing loss. Our results indicated that Kir5.1 may play an important role in the pathogenesis of AHL.
Aging ; genetics ; metabolism ; Animals ; Cations, Monovalent ; Fluorescent Antibody Technique ; Gene Expression Regulation ; Ion Transport ; Mice ; Mice, Inbred C57BL ; Microtomy ; Potassium ; metabolism ; Potassium Channels, Inwardly Rectifying ; genetics ; metabolism ; Presbycusis ; genetics ; metabolism ; physiopathology ; RNA, Messenger ; genetics ; metabolism ; Spiral Ligament of Cochlea ; metabolism ; physiopathology ; ultrastructure

The human ether-a-go-go related gene (HERG) encodes the α -subunit of the rapid component of the delayed rectifier K(+) channel, which is essential for the third repolarization of the action potential of human myocardial cells. Mutations of the HERG gene can cause type II hereditary long QT syndrome (LQT2), characterized by prolongation of the QT interval, abnormal T wave, torsade de pointes, syncope and sudden cardiac death. So far more than 300 HERG mutations have been identified, the majority of which can cause LQT2 due to HERG protein trafficking defect. It has been reported that certain drugs can induce acquired long QT syndrome through directly blocking the pore and/or affecting the HERG trafficking. The trafficking defects and K(+) currents can be restored with low temperature and certain drugs. However, the mechanisms underlying defective trafficking caused by HERG mutations and the inhibition/restoration of HERG trafficking by drugs are still unknown. This review summarizes the current understanding of the molecular mechanisms including HERG trafficking under physiological and pathological conditions, and the effects of drugs on the HERG trafficking, in order to provide theoretical evidence for the diagnosis and treatment of long QT syndrome.
Animals ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; genetics ; metabolism ; Humans ; Long QT Syndrome ; genetics ; metabolism ; physiopathology ; Protein Transport

Chloroquine ; pharmacology ; Down-Regulation ; Gene Expression ; drug effects ; HEK293 Cells ; Humans ; Leupeptins ; pharmacology ; Membrane Proteins ; antagonists & inhibitors ; genetics ; metabolism ; Microscopy, Fluorescence ; Protein Binding ; Protein Subunits ; genetics ; metabolism ; RNA Interference ; RNA, Small Interfering ; metabolism ; Shab Potassium Channels ; genetics ; metabolism

Inwardly rectifying potassium (Kir) channels exhibit an asymmetrical conductance at hyperpolarization (high conductance) compared to depolarization (low conductance). The KCNJ10 gene which encodes an inwardly rectifying K+ channel Kir4.1 subunit plays an essential role in the inner ear and hearing. Mutations or deficiency of KCNJ10 can cause hearing loss with epilepsy, ataxia, sensorineural deafness, and renal tubulopathy (EAST) or SeSAME (seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance) syndromes. In this review, we mainly focus on the expression and function of Kir4.1 channels in the inner ear and mutation-induced EAST/SeSAME syndromes to provide insight for understanding the pathogenesis of deafness induced by KCNJ10 deficiency.
Deafness ; genetics ; metabolism ; Ear, Inner ; metabolism ; Hearing Loss, Sensorineural ; genetics ; metabolism ; Humans ; Intellectual Disability ; genetics ; metabolism ; Mutation ; Potassium Channels, Inwardly Rectifying ; genetics ; metabolism ; Seizures ; genetics ; metabolism

OBJECTIVETo construct the pcDNA3-HERG-G572R expression vector and establish a cell line stably expressing HKE-HERG-G572R.

METHODSHERG-G572R mutant fragment was constructed by over-lap extension PCR and validated by DNA sequencing. The HKE-HERG-G572R expression vector was constructed and transfected into HEK293 cells to obtain a cell line stably expressing HKE-HERG-G572R.

RESULTSThe pcDNA3-HERG-G572R expression vector was successfully constructed and the cell line stably expressing HKE-HERG-G572R was established. Real-time PCR and Western blotting revealed a 632-fold HKE-HERG-G572R overexpression in the transfected HEK293 cells as compared with that in control HEK293 cells transfected with pcDNA3 (P<0.01).

CONCLUSIONThe protocol can be used to construct the cell line stably expressing HKE-HERG-G572R to provide a cell model for studying individualized therapy.

Base Sequence ; Ether-A-Go-Go Potassium Channels ; genetics ; Gene Expression ; Genetic Vectors ; HEK293 Cells ; metabolism ; Humans ; Mutation ; Transfection

OBJECTIVETo investigate the expression of GIRK4 gene in the kidney tissues of obese rats.

METHODSObese rat models were established using diet-induced method. The GIRK4 protein expression in kidney tissues was determined in 20 obese rats and 10 normal rats using Western blot analysis.

RESULTSThe relative expression level of GIRK4 protein in the kidney tissues of obese rat (1.75±0.42) was significantly lower than that in normal rats (3.37±0.68, P<0.05).

CONCLUSIONGIRK4 has a low protein expression in the kidney tissues of obese rat.

Animals ; Female ; Gene Expression ; Kidney ; metabolism ; Male ; Obesity ; genetics ; metabolism ; Potassium Channels, Inwardly Rectifying ; genetics ; metabolism ; Rats

OBJECTIVETo investigate the relationship between the G protein-gated inward rectifier K+ channel subunit 4 (GIRK4) gene polymorphism and the dyslipidemia among Uyghur residents in Xinjiang.

METHODSThe polymorphisms of rs2604204, rs4937391, rs6590357, and rs11221497 among the Uyghur residents were genotyped using Taqman polymerase chain reaction (PCR). Lipid levels were measured by conventional methods and were analyzed.

RESULTSIn the less-than-50-years population, the genotype distributions of the rs6590357 was statistically significant different in subjects with or without abnormal triglycerides (P=0.005). Aslo, the the genotype distributions of the rs11221497 also significantly differed in subjects with normal compared or abnormal TG (P=0.011). Logistic regression analysis suggested that rs6590357 still had positive association with TG abnormalities in subjects under 50 years (P=0.014). rs11221497 also had positive association with TC abnormalities. The TG levels of CT+TT genotypes were significantly higher than the CC group (P=0.006). Haplotype analysis found that the differences of H3 haplotype frequencies between the TG abnormal and normal groups were statistically significant (P=0.007).

CONCLUSIONThe polymorphisms of rs11221497 and rs6590357 of GIRK4 gene may play a role in the development of dyslipidemia in Uygur population.

China ; epidemiology ; Dyslipidemias ; epidemiology ; metabolism ; Genotype ; Humans ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Potassium Channels, Inwardly Rectifying ; genetics ; Triglycerides