The GABAA channels we study are located extrasynaptically so we have nicknamed them GABARex channels. It is very pleasing that after 15 years, we finally understand how GABA controls the conductance and the GABARex activity in brain tissue (see Lindquist and Birnir, J. Neurochem., 2006). GABARex channels are activated by about one million times lower GABA concentration than their synaptic counterparts, their conductance gradually increases in time but their maximal conductance is set by the GABA concentration. The channels are active over long periods (minutes) and generate the tonic inhibition in neurons, recently shown to significantly affect neuronal and network activity. GABA can no longer be viewed as a molecule of only synapses but rather, is also a signal molecule and is a part of the homeostatic mechanism in the brain and possible even the pancreas e.g. in type-1 diabetes, it is possible that GABA is a signalling molecule between b-cells/neurons and T-cells in the pancreas whereas relevant for type-2 diabetes, the tonic inhibition in the hypothalamus may affect the response of the neurons to metabolic hormones. As GABARex channels can be active in the absence of synaptic activity, it is possible that they are the most important pharmacological targets of drugs directed towards the GABAA receptors in the brain. But how the variable GABARex channel conductance comes about is still a mystery. Here we believe that biophysical methods can differentiate between the induced-fit or the coupled co-channels models that have been proposed.

REFERENCE

Lindquist, C.E.L. and Birnir, B. 2006. Graded response to GABA by native extrasynaptic GABAA receptors. J. Neurochem, 97, 1349-1356.