An intracellular motif of P2X sub(3) receptors is required for functional cross-talk with GABA sub(A) receptors in nociceptive DRG neurons

Functional cross-talk between structurally unrelated P2X ATP receptors and members of the 'cys-loop' receptor-channel superfamily represents a recently-discovered mechanism for rapid modulation of information processing. The extent and the mechanism of the inhibitory cross-talks between these two classes of ionotropic receptors remain poorly understood, however. Both ionic and molecular coupling were proposed to explain cross-inhibition between P2X subtypes and GABA sub(A) receptors, suggesting a P2X subunit-dependent mechanism. We show here that cross-inhibition between neuronal P2X sub(3) or P2X sub(2+3) and GABA sub(A) receptors does not depend on chloride and calcium ions. We identified an intracellular QST super(386-388) motif in P2X sub(3) subunits which is required for the functional coupling with GABA sub(A) receptors. Moreover the cross-inhibition between native P2X sub(3) and GABA receptors in cultured rat dorsal root ganglia (DRG) neurons is abolished by infusion of a peptide containing the QST motif as well as by viral expression of the main intracellular loop of GABA sub(A) beta 3 subunits. We provide evidence that P2X sub(3) and GABA sub(A) receptors are colocalized in the soma and central processes of nociceptive DRG neurons, suggesting that specific intracellular P2X sub(3)-GABA sub(A) subunit interactions underlie a pre-synaptic cross-talk that might contribute to the regulation of sensory synaptic transmission in the spinal cord.