THE REGULATION OF HEME TURNOVER AND CARBON-MONOXIDE BIOSYNTHESIS IN CULTURED PRIMARY RAT OLFACTORY RECEPTOR NEURONS

Heme oxygenase (HO) converts heme to carbon monoxide (CO) and biliverd in, which is metabolized rapidly to bilirubin. CO is implicated as an intercellular messenger, whereas bilirubin could function as an antiox idant. These cellular functions differ significantly from those of HO in peripheral tissues, in which it degrades heme from senescent erythr ocytes, suggesting that the regulation of HO may differ in neurons fro m that in other tissues. Among neurons, olfactory receptor neurons hav e the highest level of HO activity. Metabolic labeling with [2-C-14]gl ycine or delta-[H-3]aminolevulinic acid ([H-3]ALA) was used to investi gate heme metabolic turnover and CO biosynthesis in primary cultures o f olfactory receptor neurons. The production rates of heme precursors and metabolites from [C-14]glycine over 6 hr were (in pmol/mg protein) : 100 for ALA, 8.2 for heme, and 2.9 for CO. Taking into account endog enous heme content, the amount of total CO production was determined t o be 1.6 nmol/mg protein per 6 hr, Heme biosynthesis usually is subjec t to end-product negative feedback at the level of ALA synthase. Howev er, metabolic control in these neurons is different. Both heme concent ration (heme formation) and HO activity (heme degradation) were enhanc ed significantly during immature stage of neuronal differentiation in culture. Neuronal maturation, which is accelerated by transforming gro wth 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 mu M), comp arable to endogenous CO production, significantly activated guanylyl c yclase, suggesting that HO activity may regulate cGMP levels in the ne rvous system.