The essence of neuronal function is to generate outputs in response to synaptic potentials. Synaptic integration at a synapse determines neuronal outputs in the CNS. In a recent study, we describe that excitatory and inhibitory transmitter-gated channels physically crosstalk each other at the cellular and molecular level. Increased membrane expression of ATP P2X4 receptors by using an interference peptide competing with the intracellular endocytosis motif enhances neuronal excitability, which is further enhanced by reciprocal interaction between post-synaptic ATP- and GABA-gated channels. Molecular interaction is supported by experiments of co-immunoprecipitation and mutagenesis of P2X4 subunit. Two amino acids in the intracellular carboxyl tail of P2X4 subunit appears to be responsible for this crosstalk. Our recent study provides molecular and electrophysiological evidence for physical interaction between excitatory and inhibitory receptors that appears to be crucial in determining synaptic strength at central synapses.