Membrane voltage modulates the GABA(A) receptor gating in cultured rat hippocampal neurons.

Laboratory of Neuroscience, Department of Biophysics, Wrocław Medical University, ul. Chałubińskiego 3, 50-368 Wrocław, Poland.
Neuropharmacology (Impact Factor: 4.11). 03/2006; 50(2):143-53. DOI: 10.1016/j.neuropharm.2005.08.001
Source: PubMed

ABSTRACT The kinetics of GABAergic currents in neurons is known to be modulated by the membrane voltage but the underlying mechanisms have not been fully explored. In particular, the impact of membrane potential on the GABA(A) receptor gating has not been elucidated. In the present study, the effect of membrane voltage on current responses elicited by ultrafast GABA applications was studied in cultured hippocampal neurons. The current to voltage relationship (I-V) for responses to saturating [GABA] (10 mM) showed an inward rectification (slope conductance at positive voltages was 0.62 +/- 0.05 of that at negative potentials). On the contrary, I-V for currents evoked by low [GABA] (1 microM) showed an outward rectification. The onset of currents elicited by saturating [GABA] was significantly accelerated at positive potentials. Analysis of currents evoked by prolonged applications of saturating [GABA] revealed that positive voltages significantly increased the rate and extent of desensitization. The onsets of current responses to non-saturating [GABA] were significantly accelerated at positive voltages indicating an enhancement of the binding rate. However, at low [GABA] at which the onset rate is expected to approach an asymptote set by opening/closing and unbinding rates, no significant modification of current onset by voltage was observed. Quantitative analysis based on model simulations indicated that the major effect of membrane depolarization was to increase the rates of binding, desensitization and of opening as well as to slightly reduce the rate of exit from desensitization. In conclusion, we provide evidence that membrane voltage affects the GABA(A) receptor microscopic gating.

  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the analgesic effect of intrathecally administered γ-aminobutyric acid (GABA) transporter-1 inhibitor NO-711 on the sciatic nerve chronic constriction injury (CCI) rats. 5 days after intrathecal catheter placement, neuropathic pain model was established by CCI of sciatic nerve on rats. Withdrawal thresholds for mechanical allodynia and latency for thermal hyperalgesia were measured in all animals. All rats operated upon for CCI displayed decreased withdrawal thresholds for mechanical allodynia and latency for thermal hyperalgesia, which has significant difference compared with sham groups. After intrathecal NO-711 administration, withdrawal thresholds and latency were significantly increased on CCI rats compared with control group after 1 day. The results show that GABA transporter-1 inhibitor could effectively develop analgesic effect in sciatic nerve CCI rats' model.
    Neuroscience Letters 02/2011; 494(1):6-9. · 2.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ambient GABA in the brain activates GABA(A) receptors to produce tonic inhibition. Membrane potential influences both GABA transport and GABA(A) receptors and could thereby regulate tonic inhibition. We investigated the voltage dependence of tonic currents in cultured rat hippocampal neurons using patch-clamp techniques. Tonic GABA(A) conductance increased with depolarization from 15 +/- 3 pS/pF at -80 mV to 29 +/- 5 pS/pF at -40 mV. Inhibition of vesicular or nonvesicular GABA release did not prevent voltage-dependent increases of tonic conductance. Currents evoked with exogenous GABA (1 mum) were outwardly rectifying, similar to tonic currents caused by endogenous GABA. These results indicate that the voltage-dependent increase of tonic conductance was attributable to intrinsic GABA(A) receptor properties rather than an elevation of ambient GABA. After transient depolarization to +40 mV, endogenous tonic currents measured at -60 mV were increased by 75 +/- 17%. This novel form of tonic current modulation, termed postdepolarization potentiation (PDP), recovered with a time constant of 63 s, was increased by exogenous GABA and inhibited by GABA(A) receptor antagonists. Measurements of E(GABA) showed PDP was caused by increased conductance and not a change in the anion gradient. To assess the functional significance of PDP, we used voltage-clamp waveforms that replicated epileptiform activity. PDP was produced by this pathophysiological depolarization. These data show that depolarization produces prolonged potentiation of tonic conductance attributable to voltage-dependent properties of GABA(A) receptors. These properties are well suited to limit excitability during pathophysiological depolarization accompanied by rises in ambient GABA, such as occur during seizures and ischemia.
    Journal of Neuroscience 06/2010; 30(22):7672-84. · 6.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The time course of synaptic currents is a crucial determinant of rapid signaling between neurons. Traditionally, the mechanisms underlying the shape of synaptic signals are classified as pre- and post-synaptic. Over the last two decades, an extensive body of evidence indicated that synaptic signals are critically shaped by the neurotransmitter time course which encompasses several phenomena including pre- and post-synaptic ones. The agonist transient depends on neurotransmitter release mechanisms, diffusion within the synaptic cleft, spill-over to the extra-synaptic space, uptake, and binding to post-synaptic receptors. Most estimates indicate that the neurotransmitter transient is very brief, lasting between one hundred up to several hundreds of microseconds, implying that post-synaptic activation is characterized by a high degree of non-equilibrium. Moreover, pharmacological studies provide evidence that the kinetics of agonist transient plays a crucial role in setting the susceptibility of synaptic currents to modulation by a variety of compounds of physiological or clinical relevance. More recently, the role of the neurotransmitter time course has been emphasized by studies carried out on brain slice models that revealed a striking, cell-dependent variability of synaptic agonist waveforms ranging from rapid pulses to slow volume transmission. In the present paper we review the advances on studies addressing the impact of synaptic neurotransmitter transient on kinetics and pharmacological modulation of synaptic currents at inhibitory synapses.
    Frontiers in Cellular Neuroscience 01/2011; 5:6. · 4.47 Impact Factor