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

Nature volume 406, pages 405–410 (2000)Cite this article

Abstract

Transmitter-gated cation channels are detectors of excitatory chemical signals at synapses in the nervous system1. Here we show that structurally distinct α3β4 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.

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Figure 1: Non-additivity between P2X2 and α3β4 nicotinic channels.
Figure 2: P2X receptor activation results in fewer open nicotinic channels.
Figure 3: Recovery of P2X2 and α3β4 channel response additivity.
Figure 4: Inhibition of α3β4 channels revealed with a P2X2 mutant.
Figure 5: Cross-inhibition between synaptic and somatic nicotinic and P2X channels in synaptically coupled myenteric neurons.

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Acknowledgements

Thanks to H. Li for assistance with preparation of oocytes, and to other members of the group for comments. A Wellcome Trust (UK) International Prize Travelling Fellowship (to B.S.K.) and the NIH supported this work.

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Authors and Affiliations

  1. Division of Biology, California Institute of Technology, Pasadena, 91125, California, USA

    Baljit S. Khakh, Jason Sydes & Henry A. Lester

  2. Department of Pharmacology and Toxicology and the Neuroscience Program, Michigan State University, East Lansing , 48824, Michigan, USA

    Xiaoping Zhou & James J. Galligan

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  1. Baljit S. Khakh
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Correspondence to Baljit S. Khakh.

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Khakh, B., Zhou, X., Sydes, J. et al. State-dependent cross-inhibition between transmitter-gated cation channels . Nature 406, 405–410 (2000). https://doi.org/10.1038/35019066

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