Heme oxygenase (HO) converts heme to carbon monoxide (CO) and biliverdin, which is metabolized rapidly to bilirubin. CO is implicated as an intercellular messenger, whereas bilirubin could function as an antioxidant. These cellular functions differ significantly from those of HO in peripheral tissues, in which it degrades heme from senescent erythrocytes, suggesting that the regulation of HO may differ in neurons from that in other tissues. Among neurons, olfactory receptor neurons have the highest level of HO activity. Metabolic labeling with [2-14C]glycine or delta-[3H]aminolevulinic acid ([3H]ALA) was used to investigate heme metabolic turnover and CO biosynthesis in primary cultures of olfactory receptor neurons. The production rates of heme precursors and metabolites from [14C]glycine over 6 hr were (in pmol/mg protein): 100 for ALA, 8.2 for heme, and 2.9 for CO. Taking into account endogenous heme content, the amount of total CO production was determined to be 1.6 nmol/mg protein per 6 hr. Heme biosynthesis usually is subject to end-product negative feedback at the level of ALA synthase. However, metabolic control in these neurons is different. Both heme concentration (heme formation) and HO activity (heme degradation) were enhanced significantly during immature stage of neuronal differentiation in culture. Neuronal maturation, which is accelerated by transforming growth factor-beta 2 (TGF-beta 2), suppressed the activities of both heme biosynthesis and degradation. To explore the physiological importance of this endogenous production of CO, we examined the potency of CO as a soluble guanylyl cyclase activator. Exogenous CO (10-30 microM), comparable to endogenous CO production, significantly activated guanylyl cyclase, suggesting that HO activity may regulate cGMP levels in the nervous system.

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