Boué-Grabot et al. investigated the effects of coactivation of P2X2 receptors (which are excitatory) and GABAA receptors (which are inhibitory) and discovered evidence for cross inhibition that depended on subunit-specific interactions between the two receptors. γ-aminobutyric acid (GABA) and adenosine triphosphate (ATP) are co-released at brain and spinal synapses to activate colocalized GABAA and P2X receptors. Boué-Grabot et al. coexpressed GABAA receptor subunits together with P2X2 in Xenopus oocytes and recorded currents evoked by GABA and ATP. In cells expressing GABA receptors containing only α and β subunits, the channels showed reciprocal inhibition. When GABA and ATP were applied together the sum of the currents was less than predicted, and there was a smaller response to GABA administered during exposure to ATP and to ATP administered during exposure to GABA. In oocytes expressing α, β, and γ GABAA receptor subunits, however, GABA inhibited the response to ATP, whereas ATP did not inhibit the response to GABA. Reciprocal inhibition was independent of membrane potential, current direction, and the presence of calcium and was apparent with mutant GABAA receptors that were permeable to cations but not chloride. Experiments in which the authors expressed truncated or chimeric receptors or overexpressed minigenes encoding regions of the two receptors implicated the P2X2 C terminal and a GABA β3 subunit intracellular loop in the functional interaction. Moreover, only chimeric GABA receptors containing the GABA β3 intracellular loop colocalized with fluorescently labeled P2X2 when transfected into hippocampal neurons. Thus, physical interaction between the GABAA β subunit and P2X2 appears to be necessary for the functional interactions between these two receptors, and GABAA subunitcomposition may determinethe overall balance between excitation and inhibition.
É. Boué-Grabot, E. Toulmé, M. B. Émerit, M. Garret, Subunit-specific coupling between γ-aminobutyric acid type A and P2X2 receptor channels. J. Biol. Chem. 279, 52517-52525 (2004). [Abstract] [Full Text]