State-dependent cross-inhibition between transmitter-gated cation channels

Transmitter-gated cation channels are detectors of excitatory chemical sign als at synapses in the nervous system(1). Here we show that structurally di stinct alpha 3 beta 4 nicotinic and P2X(2) channels influence each other wh en co-activated. The activation of one channel type affects distinct kineti c and conductance states of the other, and co-activation results in non-add itive responses owing to inhibition of both channel types. State-dependent inhibition of nicotinic channels is revealed most clearly with mutant P2X(2 ) channels, and inhibition is decreased at lower densities of channel expre ssion. In synaptically coupled myenteric neurons, nicotinic fast excitatory postsynaptic currents are occluded during activation of endogenously co-ex pressed P2X channels. Our data provide a molecular basis and a synaptic con text for cross-inhibition between transmitter-gated channels.