Non-canonical Signaling, the Hidden Life of Ligand-Gated Ion Channels

Neuron. 2016 Oct 19;92(2):316-329. doi: 10.1016/j.neuron.2016.10.016.


Neurotransmitter receptors are responsible for the transfer of information across the synapse. While ionotropic receptors form ion channels and mediate rapid membrane depolarization, so-called metabotropic receptors exert their action though slower, less direct intracellular signaling pathways. Glutamate, GABA, and acetylcholine can activate both ionotropic and metabotropic receptors, yet the distinction between these "canonical" signaling systems has become less clear since ionotropic receptors were proposed to also activate second messenger systems, defining a "non-canonical" signaling pathway. How these alternative pathways affect neuronal circuit activity is not well understood, and their influence could be more significant than previously anticipated. In this review, we examine the evidence available that supports the existence of parallel and unsuspected signaling pathways used by ionotropic neurotransmitter receptors.

Publication types

  • Review

MeSH terms

  • Acetylcholine / metabolism
  • Glutamic Acid / metabolism
  • Humans
  • Ligand-Gated Ion Channels / metabolism*
  • Neural Pathways
  • Neurons / metabolism*
  • Neurotransmitter Agents / metabolism*
  • Receptors, GABA-A / metabolism
  • Receptors, Ionotropic Glutamate / metabolism
  • Receptors, Nicotinic / metabolism
  • Second Messenger Systems*
  • Synapses / metabolism*
  • Synaptic Transmission
  • gamma-Aminobutyric Acid / metabolism


  • Ligand-Gated Ion Channels
  • Neurotransmitter Agents
  • Receptors, GABA-A
  • Receptors, Ionotropic Glutamate
  • Receptors, Nicotinic
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Acetylcholine