Xu, TL (reprint author), Chinese Acad Sci, Inst Neurosci, Shanghai Inst Biol Sci, 320 Yue Yang Rd, Shanghai 200031, Peoples R China,
Presynaptic nerve terminals of inhibitory synapses in the dorsal horn of the spinal cord and brain stem can release both GABA and glycine, leading to coactivation of postsynaptic GABA(A) and glycine receptors. In the present study we have analyzed functional interactions between GABA(A) and glycine receptors in acutely dissociated neurons from rat sacral dorsal commissural nucleus. Although the application of GABA and glycine activates pharmacologically distinct receptors, the current induced by a simultaneous application of these two transmitters was less than the sum of currents induced by applying two transmitters separately. Sequential application of glycine and GABA revealed that the GABA-evoked current is more affected by glycine than glycine-evoked responses by GABA. Activation of glycine receptors decreased the amplitude and accelerated the rate of desensitization of GABA-induced currents. This asymmetric cross-inhibition is reversible, dependent on the agonist concentration applied, but independent of both membrane potential and intracellular calcium concentration or changes in the chloride equilibrium potential. During sequential applications, the asymmetric cross-inhibition was prevented by selective GABA(A) or glycine receptor antagonists, suggesting that occupation of binding sites did not suffice to induce glycine and GABA(A) receptors functional interaction, and receptor channel activation is required. Furthermore, inhibition of phosphatase 2B, but not phosphatase 1 or 2A, prevented GABA(A) receptor inhibition by glycine receptor activation, whereas inhibition of phosphorylation pathways rendered cross-talk irreversible. Taken together, our results demonstrated that there is an asymmetric cross-inhibition between glycine and GABA(A) receptors and that a selective modulation of the state of phosphorylation of GABA(A) receptor and/or mediator proteins underlies the asymmetry in the cross-inhibition.