Carbon Monoxide

Carbon monoxide (CO) can be synthesized by the enzyme heme oxygenase-2 (HO-2). The biological functions of CO in the nervous system include the following: modulation of long lasting changes in synaptic plasticity in the hippocampus, cerebellum, and rat superior cervical ganglion; influence of membrane excitability in olfactory receptors; modulation of the firing rate of the locus coeruleus neurons; regulation of the circadian clock; and neuroendocrine in the hypothalamus. Biochemical studies indicate that the binding of CO with the heme moiety of purified sGC results in the activation of the enzyme and increased levels of cGMP. However, much less is known about the HO/CO system in the retina and the effect of CO on retinal physiology is much less clear.

Our studies have biochemically detected HO-2 in turtle and rat retinas. HO-2 immunoreactivity is present in the inner segment of photoreceptors, in the somata of several types of amacrine, some bipolar and ganglion cells, in some cells resembling astrocytes, and in the processes in the IPL in turtle retina. HO-2 is also colocalized with cGMP in the somata of some bipolar, amacrine, and ganglion cells. These results suggest that HO-2 is widespread in the retina and that CO could be produced at many sites. The colocalization of HO-2 with cGMP strongly supports that CO could function as an endogenous modulator of the sGC/GMP signal transduction system in the retina. We have also found HO-2 and nNOS to be colocalized in many retinal neurons which strongly suggest that interactions between CO and the NO may occur. This interaction is supported by our studies demonstrating that CO can amplify the NO-induced levels of cGMP in large numbers and types of retinal neurons. Application of NOS inhibitors blocked the increases in cGMP induced by CO. These results support that CO is a modulator of the sGC/GMP signalling pathway, and that there are interactions between CO and NO on cGMP levels in the retina. More recently we have shown that these some interactions of NO and CO in the modulation of cGMP production also occur in mammalian hippocampus.