NO/cGMP-dependent modulation of synaptic transmission

Handb Exp Pharmacol. 2008;(184):529-60. doi: 10.1007/978-3-540-74805-2_16.


Nitric oxide (NO) is a multifunctional messenger in the CNS that can signal both in antero- and retrograde directions across synapses. Many effects of NO are mediated through its canonical receptor, the soluble guanylyl cyclase, and the second messenger cyclic guanosine-3',5'-monophosphate (cGMP). An increase of cGMP can also arise independently of NO via activation of membrane-bound particulate guanylyl cyclases by natriuretic peptides. The classical targets of cGMP are cGMP-dependent protein kinases (cGKs), cyclic nucleotide hydrolysing phosphodiesterases, and cyclic nucleotide-gated (CNG) cation channels. The NO/cGMP/cGK signalling cascade has been linked to the modulation of transmitter release and synaptic plasticity by numerous pharmacological and genetic studies. This review focuses on the role of NO as a retrograde messenger in long-term potentiation of transmitter release in the hippocampus. Presynaptic mechanisms of NO/cGMP/cGK signalling will be discussed with recently identified potential downstream components such as CaMKII, the vasodilator-stimulated phosphoprotein, and regulators of G protein signalling. NO has further been suggested to increase transmitter release through presynaptic clustering of a-synuclein. Alternative modes of NO/cGMP signalling resulting in inhibition of transmitter release and long-term depression of synaptic activity will also be addressed, as well as anterograde NO signalling in the cerebellum. Finally, emerging evidence for cGMP signalling through CNG channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels will be discussed.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cyclic GMP / biosynthesis
  • Cyclic GMP / pharmacology
  • Cyclic GMP / physiology*
  • Humans
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Nitric Oxide / biosynthesis
  • Nitric Oxide / pharmacology
  • Nitric Oxide / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Synapses / drug effects
  • Synapses / metabolism
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*


  • Nitric Oxide
  • Cyclic GMP