Modulation of mammalian dendritic GABAA receptor function by the kinetics of Cl- and HCO3- transport

1. During prolonged activation of dendritic GABA(A) receptors, the postsynaptic membrane response changes from hyperpolarization to depolarization. One explanation for the change in direction of the response is that opposing HCO3- and Cl- fluxes through the GABA(A) ionophore diminish the electrochemical gradient driving the hyperpolarizing Cl- flux, so that the depolarizing HCO3- flux dominates. Here we demonstrate that the necessary conditions for this mechanism are present in rat hippocampal CA1 pyramidal cell dendrites. 2. Prolonged GABA(A) receptor activation in low-HCO3- media decreased the driving force for dendritic but not somatic Cl- currents. Prolonged GABA(A) receptor activation in low-Cl- media containing physiological HCO3- concentrations did not degrade the driving force for dendritic or somatic HCO3- gradients. 3. Dendritic Cl- transport was measured in three ways: from the rate of recovery of GABA(A) receptor-mediated currents between paired dendritic GABA applications, from the rate of recovery between paired synaptic GABA(A) receptor-mediated currents, and from the predicted vs. actual increase in synaptic GABA(A), receptor-mediated currents at progressively more positive test potentials. These experiments yielded estimates of the maximum transport rate (upsilon(max)) for Cl- transport of 5 to 7 mmol l(-1) s(-1), and indicated that upsilon(max) could be exceeded by GABA(A) receptor-mediated Cl- influx. 4. The affinity of the Cl- transporter was calculated in experiments in which the reversal potential for Cl- (E-Cl) mas measured from the GABA(A) reversal potential in low-HCO3- media during Cl- lending from the recording electrode solution. The calculated K-D was 15 mM. 5. Using a standard model of membrane potential, these conditions are demonstrated to be sufficient to produce the experimentally observed, activity-dependent GABA(A) depolarizing response in pyramidal cell dendrites.