Extracellular Signal-Regulated Kinases Mediate an Autoregulation of GABA-Receptor-Activated Whole-Cell Current in Locus Coeruleus Neurons.

The norepinephrine-releasing neurons in the locus coeruleus (LC) are well known to regulate wakefulness/arousal. They display active firing during wakefulness and a decreased discharge rate during sleep. We have previously reported that LC neurons express large numbers of GABA receptors (GABARs) located at peri-/extrasynaptic sites and are subject to tonic inhibition due to the continuous activation of GABARs by ambient GABA, which is significantly higher during sleep than during wakefulness. In this study, we further showed using western blot analysis that the activation of GABARs with baclofen could increase the level of phosphorylated extracellular signal-regulated kinase 1 (ERK) in LC tissue. Recordings from LC neurons in brain slices showed that the inhibition of ERK with U0126 and FR180204 accelerated the decay of whole-cell membrane current induced by prolonged baclofen application. In addition, the inhibition of ERK also increased spontaneous firing and reduced tonic inhibition of LC neurons after prolonged exposure to baclofen. These results suggest a new role of GABARs in mediating ERK-dependent autoregulation of the stability of GABAR-activated whole-cell current, in addition to its well-known effect on gated potassium channels, to cause a tonic current in LC neurons.