Epilepsies associated with KCNQ2 : A spectrum of disorders / 中国医师杂志

Epilepsies associated with KCNQ2 are a spectrum of disorders,and KCNQ2 mutations lead to a variety of phenotypes from the severest to the mildest,from early onset epileptic encephalopathy (EOEE) to benign familial neonatal convulsion (BFNC).The type and the position of KCNQ2 mutations may be associated with phenotypes,and provide a clue for assessing prognosis.KCNQ2 mutations lead to the reduced protein expression,abnormal distribution of potassium channels or decreased currents of potassium channels.It is the potential mechanism that KCNQ2 mutations cause different phenotypes.Recent studies have also found that KCNQ2 mutations may trigger seizures by enhancing potassium channel currents;however it needs further studies to verify.

Effects of different concentrations of chloroprocaine on KCNQ2/Q3 channel currents in HEK2936 cells / 中华麻醉学杂志

Objective To evaluate the effects of different concentrations of chloroprocaine on KCNQ2/Q3 channel currents in HEK2936 cells.Methods Human embryonic kidney (HEK293) cells served as an expression system.KCNQ2 and KCNQ3 cDNAs and green fluorescent protein were transfected into HEK293 cells by using lipofectamine.The KCNQ2/Q3 currents were recorded by using the whole-cell patch-clamp technique.Part Ⅰ The transfected HEK293 cells were randomly divided into 4 groups (n =11 each):control group,and 1,10 and 100 mmol/L chloroprocaine groups.The KCNQ2/Q3 channel currents produced by different concentrations of chloroprocaine were recorded under different holding potentials (-40,0 and 40 mV) and the action time was 1 min.Part Ⅱ The transfected HEK293 cells were randomly divided into 2 groups (n =5 each):control group and 10 mmol/L chloroprocaine.The KCNQ2/Q3 channel currents were recorded under different holding potentials (-80-30 mV)and the action time was 1 min.Different test potentials were normalized and fitted to Boltzmann function,and KCNQ2/Q3 channel Ⅰ-Ⅴ curve was then obtained.The activation and deactivation currents were both fitted to a single exponential function and the time constants for current activation and for current deactivation were calculated.Results Part Ⅰ When the holding potential was 40,0 and-40 mV,the suppression rate of KCNQ2/Q3 channel currents in HEK293 cells was higher in 1,10 and 100 mmol/L chloroprocaine groups than in control group (P ＜0.05 or 0.01).Part Ⅱ Compared with control group,the time constant for the current activation at 0 mV of holding potential was prolonged,the time constant for the current deactivation was shortened when the holding potential was-80 mV,and the half-activation voltage of KCNQ2/Q3 channels was increased,the activation curve shifted to the depolarized potentials,and KCNQ2/Q3 channel Ⅰ-Ⅴ curve slope was decreased in 10 mmol/L chloroprocaine group (P ＜ 0.05).Conclusion Chloroprocaine concentration-dependently suppresses KCNQ2/Q3 channel currents in HEK2936 cells.The KCNQ2/Q3 channel is closed in advance due to KCNQ2/Q3 channel opening delay induced by chloroprocaine thus decreasing the activity of KCNQ2/Q3 channels.

Effect of retigabine on median effective dose of bupivacaine and chloroprocaine for induction of convulsion in mice / 中华麻醉学杂志

Objective To investigate the effect of KCNQ2/3 channel opener retigabine on the median effective dose (ED50) of bupivacaine and chloroprocaine for induction of convulsion in mice and the relationship between KCNQ2/3 channels and the neurotoxicity of local anesthetics.Methods Pathogen-free female Kunming mice,weighing 20-30 g,were used in the study.The experiment was performed in two parts.Part Ⅰ Sixty mice were randomly divided into 2 groups (n =30 each):control group (group C) and retigabine group (group R).The C and R groups were further divided into 3 subgroups with different doses of chlorprocaine (C + L1,C + L2 and C+ L3 groups,and R+ L1,R+ L2 and R+ L3 groups,n =10 each).In groups C and R,0.9％ normal saline 0.005 ml/g and retigabine 20 mg/kg were injected intraperitoneally,respectively,and chlorprocaine was injected intraperitoneally 20 min later.The doses of chlorprocaine were 150.0,172.5 and 198.4 mg/kg in C + L1,C + L2 and C + L3 groups,respectively,and 198.4,228.2 and 262.4 mg/kg in R+ L1,R+ 12 and R+ L3 groups,respectively.Part Ⅱ Eighty mice were randomly divided into 2 groups (n =40 each):control group (group C) and retigabine group (group R).The C and R groups were further divided into 4 subgroups with different doses of bupivacaine (C + B1,C + B2,C + B3 and C + B4 groups,and R + B1,R + B2,R + B3 and R + B4 groups,n =10 each).In groups C and R,0.9％ normal saline 0.005 ml/g and retigabine 20 mg/kg were injected intraperitoneally,respectively,and bupivacaine was injected intraperitoneally 20 min later.The doses of bupivacaine were 37.8,43.5,50.0 and 57.5 mg/kg in C + B1,C + B2,C + B3 and C + B4 groups,respectively,and 50.0,57.5,66.1 and 76.0 mg/kg in R + B1,R + B2,R + B3 and R + B4 groups,respectively.The ED50 and 95％ confidence interval (CI) of bupivacaine and chloroprocaine for induction of convulsion were calculated by Probit analysis.Results The ED50(95％ CI) of chloroprocaine was 165.3 (155.8-175.0) mg/kg,and the ED50(95％CI) of bupivacaine was 41.1 (36.7-44.5) mg/kg in C group.The ED50 (95％ CI) of chloroprocaine was 212.4 (200.2-224.3) mg/kg,and the ED5o (95％ CI)of bupivacaine was 51.5 (945.1-56.0)mg/kg in R group.Compared with group C,the ED50 of bupivacaine and chloroprocaine for induction of convulsion was significantly increased in group R (P ＜ 0.01).Conclusion KCNQ2/3 channel opener retigabine can significantly increase the ED50 of bupivacaine and chloroprocaine for induction of convulsion and reduce convulsion induced by bupivacaine and chloroprocaine in mice,indicating that the neurotoxicity of local anesthetics is related to inhibition of KCNQ2/3 channels.

The First Korean Case of KCNQ2 Mutation in a Family with Benign Familial Neonatal Convulsions

Neonatal seizures represent a heterogeneous group of disorders with vastly different etiologies and outcomes. Benign familial neonatal convulsions (BFNC) are a distinctive epileptic syndrome of autosomal dominant inheritance with a favorable prognosis, characterized by the occurrence of unprovoked partial or generalized clonic seizures in the neonatal period or early infancy. Recently, mutations in two potassium channel genes, KCNQ2 and KCNQ3, have been described in this disorder. In this report, we describe a family with BFNC due to a KCNQ2 mutation, the first such family to be described in the Korean population. The diagnosis of BFNC can be made based on clinical suspicion and careful history taking with special emphasis on the familial nature of the disorder. KCNQ2 mutations may be associated with BFNC in a number of different races, as has been reported in other ethnic groups.