The heme oxygenase/carbon monoxide system in the retina: Biochemistry, anatomy and interactions with the nitric oxide/cGMP pathway

Neuronal communications mediated by gaseous molecules like nitric oxide (NO) or carbon monoxide (CO) represent novel types of neurotransmission.{09}NO and CO are synthesized by nitric oxide synthase (NOS) and heme oxygenase (HO), respectively. Both NO and CO can activate soluble guanylate cyclase (sGC) to increase cGMP levels. The present study used a combination of in vitro incubations and immunocytochemistry to examine the anatomical localization of HO and the biochemical and physiological effects of CO in the retina.{09}The results indicated that HO-2, the constitutive isoform of HO, was present in many types of retinal neurons in turtle and several mammalian species.{09}HO-2 was partially colocalized with sGC activity in turtle, and with neuronal NOS (nNOS) in many species. The physiological studies in turtle retina indicated that CO alone slightly increased cGMP levels in some bipolar and amacrine cells.{09}CO also had an amplification effect on NO-induced increases in cGMP in many neurons. Surprisingly, NOS inhibitors were able to block all the CO stimulated increases in cGMP.; Ultrastructural investigations in turtle retina indicated that nNOS could be diffusely localized in the cytoplasm, or it could be more selectively associated with the endoplasmic and nuclear membranes, and with some atypical and conventional mitochondria. In amacrine and bipolar cell synaptic terminals, nNOS was selectively localized at synaptic specializations. These results suggest that NO may play diverse roles in retinal neurons, and that NO may modulate synaptic activity at the level of single active zones.; The present study provided the first localization of HO-2 in the retinas of many species. It also confirmed and extended the hypothesis that CO interacts with NO to modulate the NO/cGMP signal transduction pathway. The anatomical result correlates well with the widespread NO production found in previous NO imaging studies. Finally, the results imply that CO might be an intercellular and intracellular messenger in the retina, and that the interactions between CO and the NO/cGMP pathway may occur in the retinas of many species.