Characterization of nitric oxide signaling pathways in the mouse retina

J Comp Neurol. 2012 Dec 15;520(18):4204-17. doi: 10.1002/cne.23148.


Nitric oxide (NO) is a gaseous neuromodulator with physiological functions in every retinal cell type. NO is synthesized by several nitric oxide synthases (NOS) and often functions through its second messenger, cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG). This study combined NO imaging, immunocytochemistry, biochemistry, and molecular biology to localize NO and its downstream signaling pathways in the mouse retina. Neuronal NOS (nNOS) was localized primarily in puncta in the inner plexiform layer, in amacrine cells, and in somata in the ganglion cell layer. Endothelial NOS was in blood vessels. Light-stimulated NO production imaged with diaminofluorescein was present in somata in the inner nuclear layer and in synaptic boutons in the inner plexiform layer. The downstream target of NO, soluble guanylate cyclase (sGC), was in somata in the inner and outer nuclear layers and in both plexiform layers. Cyclic GMP immunocytochemistry was used functionally to localize sGC that was activated by an NO donor in amacrine, bipolar, and ganglion cells. Cyclic GMP-dependent protein kinase (PKG) Iα was found in bipolar cells, ganglion cells, and both plexiform layers, whereas PKG II was found in the outer plexiform layer, amacrine cells, and somata in the ganglion cell layer. This study shows that the NO/cGMP/PKG signaling pathway is functional and widely distributed in specific cell types in the outer and inner mouse retina. A better understanding of these signaling pathways in normal retina will provide a firm basis for targeting their roles in retinal pathology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Animals
  • Calbindins
  • Cyclic GMP / metabolism
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Guanylate Cyclase / metabolism
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / metabolism
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism
  • Phosphodiesterase Inhibitors / pharmacology
  • Protein Kinase C / classification
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Retina / anatomy & histology
  • Retina / drug effects
  • Retina / metabolism*
  • S-Nitroso-N-Acetylpenicillamine / pharmacology
  • S100 Calcium Binding Protein G / metabolism
  • Signal Transduction / physiology*
  • Soluble Guanylyl Cyclase
  • Visual Pathways / drug effects
  • Visual Pathways / metabolism


  • Calbindins
  • Nerve Tissue Proteins
  • Phosphodiesterase Inhibitors
  • Receptors, Cytoplasmic and Nuclear
  • S100 Calcium Binding Protein G
  • Nitric Oxide
  • S-Nitroso-N-Acetylpenicillamine
  • Nitric Oxide Synthase
  • Protein Kinase C
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase
  • Cyclic GMP
  • 1-Methyl-3-isobutylxanthine