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Hua-Jun Feng

Publications and source records attributed to Hua-Jun Feng.

9 recordsLinked to original sources
PubMed2006

Delta subunit susceptibility variants E177A and R220H associated with complex epilepsy alter channel gating and surface expression of alpha4beta2delta GABAA receptors.

Most human idiopathic generalized epilepsies (IGEs) are polygenic, but virtually nothing is known of the molecular basis for any of the complex epilepsies. Recently, two GABAA receptor delta subunit variants (E177A, R220H) were proposed as susceptibility alleles for generalized epilepsy with febrile seizures plus and juvenile myoclonic epilepsy. In human embryonic kidney 293T cells, recombinant halpha1beta2delta(E177A) and halpha1beta2delta(R220H) receptor currents were reduced, but the basis for the current reduction was not determined. We examined the mechanistic basis for the current reduction produced by these variants using the halpha4beta2delta receptor, an isoform more physiologically relevant and linked to epileptogenesis, by characterizing the effects of these variants on receptor cell surface expression and single-channel gating properties. Expression of variant alpha4beta2delta(R220H) receptors resulted in a decrease in surface receptor proteins, and a smaller, but significant, reduction was observed for variant alpha4beta2delta(E177A) receptors. For both variants, no significant alterations of surface expression were observed for mixed population of wild-type and variant receptors. The mean open durations of alpha4beta2delta(E177A) and alpha4beta2delta(R220H) receptor single-channel currents were both significantly decreased compared to wild-type receptors. These data suggest that both delta(E177A) and delta(R220H) variants may result in disinhibition in IGEs by similar cellular and molecular mechanisms, and in heterozygously affected individuals, a reduction in channel open duration of delta subunit-containing GABAA receptors may be the major contributor to the epilepsy phenotypes.

Amino Acid Substitution↗
PubMed2005

Effect of easily degradable substrate on anaerobic degradation of pentachlorophenol in an upflow anaerobic sludge blanket (UASB) reactor.

The effect of microbial easily degradable substrate (MEDS) on the anaerobic degradation of pentachlorophenol (PCP) in two upflow anaerobic sludge blanket (UASB) reactors was investigated. The results indicated that glucose-utilizing activity decreased with the increase of PCP concentration in the mixed culture, and MEDS promoted PCP-dechlorination and degrading activities. The concentration of MEDS increased from 917 to 4580 mg L(-1) with the increase of PCP concentration from 100 to 181 mg L(-1)in influent, which was necessary for maintenance of steady operation of the experimental reactors, the removal rate of PCP and COD ranged up to 99.5 and 90.0% and the concentration of PCP in the effluent was less than 0.5 mg L(-1). The concentration of PCP in effluent was linearly or logarithmically related to sucrose concentration in the influent while PCP was less than the maximum permissible PCP concentration. The activity of anaerobic sludge in the reactor decreased as the concentration of PCP increased, but it could be recovered step by step as time progressed. In the lowest layer of the reactor, the activity of sludge was the highest. So it is feasible to accelerate the degradation of the organic toxic compounds like PCP, by adding suitable quantities of microbial easily degradable substrate to the system.

Bacteria, Anaerobic↗
PubMed2004

GABA(A) receptor epilepsy mutations.

Idiopathic generalized epilepsy (IGE) syndromes are diseases that are characterized by absence, myoclonic, and/or primary generalized tonic-clonic seizures in the absence of structural brain abnormalities. Although it was long hypothesized that IGE had a genetic basis, only recently have causative genes been identified. Here we review mutations in the GABA(A) receptor alpha1, gamma2, and delta subunits that have been associated with different IGE syndromes. These mutations affect GABA(A) receptor gating, expression, and/or trafficking of the receptor to the cell surface, all pathophysiological mechanisms that result in neuronal disinhibition and thus predispose affected patients to seizures.

Epilepsy↗
PubMed2004

Multiple actions of propofol on alphabetagamma and alphabetadelta GABAA receptors.

GABAA receptors are predominantly composed of alphabetagamma and alphabetadelta isoforms in the brain. It has been proposed that alphabetagamma receptors mediate phasic inhibition, whereas alphabetadelta receptors mediate tonic inhibition. Propofol (2,6-di-isopropylphenol), a widely used anesthetic drug, exerts its effect primarily by modulating GABAA receptors; however, the effects of propofol on the kinetic properties of alphabetagamma and alphabetadelta receptors are uncertain. We transfected human embryonic kidney (HEK293T) cells with cDNAs encoding rat alpha1, alpha6, beta3, gamma2L, or delta subunits and performed whole-cell patch-clamp recordings to explore this issue. Propofol (3 microM) increased GABA concentration-response curve maximal currents similarly for both alpha1beta3gamma2L and alpha6beta3gamma2L receptors, but propofol increased those for alpha1beta3delta and alpha6beta3delta receptors differently, the increase being greater for alpha1beta3delta than for alpha6beta3delta receptors. Propofol (10 microM) produced similar alterations in alpha1beta3gamma2L and alpha6beta3gamma2L receptor currents when using a preapplication protocol; peak currents were not altered, desensitization was reduced, and deactivation was prolonged. Propofol enhanced peak currents for both alpha1beta3delta and alpha6beta3delta receptors, but the enhancement was greater for alpha1beta3delta receptors. Desensitization of these two isoforms was not modified by propofol. Propofol did not alter the deactivation rate of alpha1beta3delta receptor currents but did slow deactivation of alpha6beta3delta receptor currents. The findings that propofol reduced desensitization and prolonged deactivation of gamma2L subunit-containing receptors and enhanced peak currents or prolonged deactivation of delta subunit-containing receptors suggest that propofol enhancement of both phasic and tonic inhibition may contribute to its anesthetic effect in the brain.

Cell Line↗
PubMed2004

Pentobarbital differentially modulates alpha1beta3delta and alpha1beta3gamma2L GABAA receptor currents.

GABAA receptors are modulated by a variety of compounds, including the neurosteroids and barbiturates. Although the effects of barbiturates on alphabetagamma isoforms, thought to dominate phasic (synaptic) GABAergic inhibition, have been extensively studied, the effects of pentobarbital on kinetic properties of alphabetadelta GABAA receptors, thought to mediate tonic (extra- or perisynaptic) inhibition, are unknown. Using ultrafast drug delivery and single channel recording techniques, we demonstrate isoform-specific pentobarbital modulation of low-efficacy, minimally desensitizing alpha1beta3 currents and high-efficacy, rapidly desensitizing alpha1beta3gamma2L currents. Specifically, with saturating concentrations of GABA, pentobarbital substantially potentiated peak alpha1beta3delta receptor currents but failed to potentiate peak alpha1beta3gamma2L receptor currents. Also, pentobarbital had opposite effects on the desensitization of alpha1beta3delta (increased) and alpha1beta3gamma2L (decreased) receptor currents evoked by saturating GABA. Pentobarbital increased steady-state alpha1beta3delta receptor single channel open duration primarily by introducing a longer duration open state, whereas for alpha1beta3gamma2L receptor channels, pentobarbital increased mean open duration by increasing the proportion and duration of the longest open state. The data support previous suggestions that GABA may be a partial agonist at alphabetadelta isoforms, which may render them particularly sensitive to allosteric modulation. The remarkable increase in gating efficacy of alpha1beta3delta receptors suggests that alphabetadelta isoforms, and by inference tonic forms of inhibition, may be important targets for barbiturates.

Cells, Cultured↗
PubMed2004

Proton modulation of alpha 1 beta 3 delta GABAA receptor channel gating and desensitization.

Alphabetagamma GABA(A) receptor currents are phasic and desensitizing, whereas alphabetadelta GABA(A) receptor currents are tonic and have no fast desensitization. alphabetagamma receptors are subsynaptic and mediate phasic inhibition, whereas alphabetadelta receptors are extra- or perisynaptic and mediate tonic inhibition. Given the different roles of these GABA(A) receptor isoforms and the fact that GABA(A) receptors are allosterically regulated by extracellular pH in a subunit-dependent manner, we compared the effects of changing pH on rat delta or gamma2L subunit-containing GABA(A) receptor currents. Human embryonic kidney cells (HEK293T) were transfected with cDNAs encoding rat alpha1, beta3, gamma2L, or delta GABA(A) receptor subunits in several binary and ternary combinations, and whole cell and single channel patch-clamp recordings were obtained. Lowering pH substantially enhanced alpha1beta3 receptor currents. This effect was significantly more pronounced for ternary alpha1beta3delta receptors, whereas ternary alpha1beta3gamma2L receptors were relatively insensitive to lowered pH. Lowering pH did not affect the extent of desensitization of alpha1beta3 and alpha1beta3gamma2L receptor currents, but significantly increased the extent of desensitization of alpha1beta3delta receptor currents. Lowering pH prolonged deactivation of alpha1beta3 and alpha1beta3delta receptor currents and enhanced the "steady-state" currents of alpha1beta3delta receptors evoked by long-duration (28 s) GABA applications. Lowering pH significantly increased mean open duration of alpha1beta3delta steady-state single channel currents due to introduction of a longer-duration open state, suggesting that low pH enhances alpha1beta3delta receptor steady-state currents by modifying GABA(A) receptor gating properties.

Cell Line↗
PubMed2004

GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies.

A major challenge in understanding complex idiopathic generalized epilepsies has been the characterization of their underlying molecular genetic basis. Here, we report that genetic variation within the GABRD gene, which encodes the GABAA receptor delta subunit, affects GABA current amplitude consistent with a model of polygenic susceptibility to epilepsy in humans. We have found a GABRD Glu177Ala variant which is heterozygously associated with generalized epilepsy with febrile seizures plus. We also report an Arg220His allele in GABRD which is present in the general population. Compared with wild-type receptors, alpha1beta2Sdelta GABAA receptors containing delta Glu177Ala or Arg220His have decreased GABAA receptor current amplitudes. As GABAA receptors mediate neuronal inhibition, the reduced receptor current associated with both variants is likely to be associated with increased neuronal excitability. Since delta subunit-containing receptors localize to extra- or peri-synaptic membranes and are thought to be involved in tonic inhibition, our results suggest that alteration of this process may contribute to the common generalized epilepsies.

Amino Acid Substitution↗
PubMed2002

Synaptic plasticity in the pathway from the medial geniculate body to the lateral amygdala is induced by seizure repetition.

Repeated induction of generalized audiogenic seizures (AGS) (AGS kindling) induces expansion of the seizure network and evokes additional convulsive behaviors. The medial geniculate body (MGB) and amygdala are implicated in the network expansion induced by AGS kindling, although these sites are not required for AGS before kindling. A recent study indicated that amygdala neuronal responses are greatly increased by AGS kindling. The present study examined the effects of AGS kindling on the thalamo-amygdala pathway in genetically epilepsy-prone rats (GEPR-9s) by examining the neuronal responses in lateral amygdala (LAMG) to electrical stimulation in MGB in vivo. AGS kindling in GEPR-9s involved 14 AGS in response to twice daily acoustic stimulation. Sham-kindled normals received the mean stimulation parameters presented to kindled animals. Spontaneous LAMG extracellular action potentials (APs) and APs evoked by electrical stimuli in the MGB were examined in ketamine-anesthetized rats. The mean spontaneous LAMG firing in kindled GEPR-9s was significantly elevated as compared to non-kindled GEPRs, sham-kindled and non-kindled normals. LAMG firing evoked by MGB stimuli in kindled GEPR-9s was significantly elevated, and a significant mean threshold reduction was also observed in kindled GEPR-9s, as compared to other animal groups. These changes may be due to enhanced glutamate receptor-mediated excitation and/or compromised GABA receptor-mediated inhibition in AMG, as previously reported in electrical kindling in the amygdala. These findings indicate that AGS kindling increases the efficacy of the thalamo-amygdala pathway in GEPR-9s, suggesting that synaptic plasticity in this portion of the expanded neuronal network is an important pathophysiological mechanism subserving AGS kindling.

Acoustic Stimulation↗