Modulation of synaptic function by cGMP and cGMP-gated cation channels

Colin Barnstable, Ji Ye Wei, Ming Hu Han

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Cyclic nucleotide-gated cation channels have been studied intensively in the primary sensory neurons of the visual and olfactory systems. Using both anatomical and physiological methods we have shown that they have a much more widespread distribution in the nervous system. In many retinal ganglion cells cGMP, but not cAMP, activates a non-selective conductance that has many of the properties of CNG channels. As many neurons also contain cGMP-dependent protein kinases (PKGs), we have used a variety of cGMP analogues to distinguish the actions of cGMP. Sp-8-Br-PET-cGMPS is a potent non-hydrolyzable cGMP analogue that is an agonist of PKG. We found that Sp-8-Br-PET-cGMPS acts as a competitive inhibitor of at least the rod CNG channel. Rp-8-Br-cGMPS has shown the opposite effects, namely as an agonist of the rod CNG channel and an inhibitor of PKG. In dissociated cell cultures and slices of rodent visual cortex cGMP had multiple rapid and reversible effects on transmission at glutamatergic synapses. Extracellular application of 8-Br-cGMP or Sp-8-Br-PET-cGMPS reduced stimulus evoked EPSPs in cortical slices. In cortical cultures both analogs reduced the frequency of spontaneous EPSCs, but not their amplitude. The effects on both EPSPs and EPSCs were presynaptic. The effects on evoked EPSPs may be due, in part, to reduced calcium influx through voltage-gated calcium channels. The effects on spontaneous EPSCs may be due, in part, to modulation of calcium fluxes through internal stores. Similar modulations of synaptic transmission have been found at gabaergic synapses. On postsynaptic cells, PKG activation produced a dramatic enhancement of the responses to applied NMDA. No effects were detected on applied AMPA/kainate or GABA. Together the results suggest that cGMP may use multiple mechanisms to modulate synaptic efficacy and that its actions may include regulating synaptic plasticity and the relative strength of excitatory and inhibitory drive through neural pathways.

Original languageEnglish (US)
Pages (from-to)875-884
Number of pages10
JournalNeurochemistry International
Volume45
Issue number6
DOIs
StatePublished - Nov 1 2004

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Cyclic Nucleotide-Gated Cation Channels
Cations
Excitatory Postsynaptic Potentials
Synapses
Olfactory Receptor Neurons
Calcium
Cyclic GMP-Dependent Protein Kinases
Neural Pathways
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Neuronal Plasticity
Retinal Ganglion Cells
Kainic Acid
Visual Cortex
N-Methylaspartate
Calcium Channels
Synaptic Transmission
gamma-Aminobutyric Acid
Nervous System
Rodentia
Cell Culture Techniques

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

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abstract = "Cyclic nucleotide-gated cation channels have been studied intensively in the primary sensory neurons of the visual and olfactory systems. Using both anatomical and physiological methods we have shown that they have a much more widespread distribution in the nervous system. In many retinal ganglion cells cGMP, but not cAMP, activates a non-selective conductance that has many of the properties of CNG channels. As many neurons also contain cGMP-dependent protein kinases (PKGs), we have used a variety of cGMP analogues to distinguish the actions of cGMP. Sp-8-Br-PET-cGMPS is a potent non-hydrolyzable cGMP analogue that is an agonist of PKG. We found that Sp-8-Br-PET-cGMPS acts as a competitive inhibitor of at least the rod CNG channel. Rp-8-Br-cGMPS has shown the opposite effects, namely as an agonist of the rod CNG channel and an inhibitor of PKG. In dissociated cell cultures and slices of rodent visual cortex cGMP had multiple rapid and reversible effects on transmission at glutamatergic synapses. Extracellular application of 8-Br-cGMP or Sp-8-Br-PET-cGMPS reduced stimulus evoked EPSPs in cortical slices. In cortical cultures both analogs reduced the frequency of spontaneous EPSCs, but not their amplitude. The effects on both EPSPs and EPSCs were presynaptic. The effects on evoked EPSPs may be due, in part, to reduced calcium influx through voltage-gated calcium channels. The effects on spontaneous EPSCs may be due, in part, to modulation of calcium fluxes through internal stores. Similar modulations of synaptic transmission have been found at gabaergic synapses. On postsynaptic cells, PKG activation produced a dramatic enhancement of the responses to applied NMDA. No effects were detected on applied AMPA/kainate or GABA. Together the results suggest that cGMP may use multiple mechanisms to modulate synaptic efficacy and that its actions may include regulating synaptic plasticity and the relative strength of excitatory and inhibitory drive through neural pathways.",
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Modulation of synaptic function by cGMP and cGMP-gated cation channels. / Barnstable, Colin; Wei, Ji Ye; Han, Ming Hu.

In: Neurochemistry International, Vol. 45, No. 6, 01.11.2004, p. 875-884.

Research output: Contribution to journalArticle

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