Voltage-dependent modulation of GABAA receptor channel desensitization in rat hippocampal neurons.

1. The mechanism of the time-dependent decline in gamma-amino-butyric acid (GABA)-induced chloride conductance, referred to as desensitization, was studied in dissociated rat hippocampal cell culture with the use of a whole-cell voltage-clamp recording. 2. In most cells the gradual decline of membrane conductance was dependent simultaneously on the agonist concentration and membrane voltage. Even in the continued presence of GABA, desensitization could be prevented by holding the membrane potential > 0 mV in a near symmetrical chloride gradient across the cell membrane. 3. The "recovery" from desensitization occurred after removal of the agonist with a time constant of approximately 35 s. The rate of recovery from desensitization was independent of membrane voltage. 4. When the membrane potential was jumped from a negative to a positive membrane potential during steady state of desensitization, the GABA-induced chloride conductance gradually "relaxed" to the undesensitized state. This phenomenon of gradual increase in chloride conductance or "reactivation" from desensitization was both voltage and agonist dependent. 5. The process of recovery of the GABA ionophore from the desensitized state is distinct from the process of reactivation, which is dependent both on the voltage and agonist. 6. These observations suggest that the ligand-bound GABA receptor has two alternate states, i.e., permissive (activated) and desensitized. The rates of transition between these two states are voltage dependent.