GABA-B Controls Persistent Na⁺ Current and Coupled Na⁺-Activated K⁺ Current

Abstract

The GABA-B receptor is densely expressed throughout the brain and has been implicated in many CNS functions and disorders including addiction, epilepsy, spasticity, schizophrenia, anxiety, cognitive deficits, and depression, as well as various aspects of nervous system development. How one GABA-B receptor is involved in so many aspects of CNS function remains unanswered. Activation of GABA-B receptors is normally thought to produce inhibitory responses in the nervous system but puzzling contradictory responses exist. Here we report that in rat mitral cells of the olfactory bulb GABA-B receptor activation inhibits both the persistent sodium current (INa_P) and the sodium-activated potassium current (IK_Na) which is coupled to it. We find that the primary effect of GABA-B activation is to inhibit INa_P which has the secondary effect of inhibiting IK_Na because of its dependence on persistent sodium entry for activation. This can have either a net excitatory or inhibitory effect depending on the balance of INa_P/IK_Na currents in neurons. In the olfactory bulb the cell bodies of mitral cells are densely packed with sodium-activated potassium channels. These channels produce a large IK_Na which, if constitutively active, would shunt any synaptic potentials traversing the soma before reaching the spike initiation zone. However, GABA-B receptor activation might have the net effect of reducing the IK_Na blocking effect, thus enhancing the effectiveness of synaptic potentials.

Significance Statement The GABA-B receptor is densely expressed in brain and implicated in many CNS functions and disorders but knowledge of its mode of action is limited. We have found a novel action whereby GABA-B receptor activity inhibits two opposing currents, the persistent sodium current and the sodium-activated potassium current that is activated by it. It is likely that GABA-B receptor activation through this coupled system of currents can have either a net excitatory or inhibitory response depending on the balance of currents. Extensive co-localization of GABA-B receptors and sodium-activated potassium channels throughout the nervous system suggests a significant mechanism for GABA-B neuromodulation and our results suggests new insights for controlling cell excitability through GABA-B modulators.