State-dependent cross-inhibition between transmitter-gated cation channels.
Transmitter-gated cation channels are detectors of excitatory chemical signals at synapses in the nervous system. Here we show that structurally distinct alpha3beta4 nicotinic and P2X2 channels influence each other when co-activated. The activation of one channel type affects distinct kinetic and conductance states of the other, and co-activation results in non-additive responses owing to inhibition of both channel types. State-dependent inhibition of nicotinic channels is revealed most clearly with mutant P2X2 channels, and inhibition is decreased at lower densities of channel expression. In synaptically coupled myenteric neurons, nicotinic fast excitatory postsynaptic currents are occluded during activation of endogenously co-expressed P2X channels. Our data provide a molecular basis and a synaptic context for cross-inhibition between transmitter-gated channels.
Division of Biology, California Institute of Technology, Pasadena 91125, USA. balkhakh@its.caltech.edu
B S
BS
Khakh
X
X
Zhou
J
J
Sydes
J J
JJ
Galligan
H A
HA
Lester
D000109:Acetylcholine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D015640:Ion Channel Gating; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000494:pharmacology; D020239:Receptor Cross-Talk; D011978:Receptors, Nicotinic / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058476:Receptors, Purinergic P2X2; D011994:Recombinant Proteins / Q000378:metabolism; D013569:Synapses; D014981:Xenopus
D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D018048:Receptors, Purinergic P2; D058476:Receptors, Purinergic P2X2; D011994:Recombinant Proteins; C403530:nicotinic receptor alpha3beta4; C012647:QX-314; D000255:Adenosine Triphosphate; D008012:Lidocaine; D000109:Acetylcholine