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Volume 16, Number 18,
Issue of September 15, 1996
pp. 5621-5628
Copyright ©1996 Society for Neuroscience
The Regulation of Heme Turnover and Carbon Monoxide Biosynthesis
in Cultured Primary Rat Olfactory Receptor Neurons
Received March 18, 1996; revised June 17, 1996; accepted June 28, 1996.
Tatsuya Ingi1,
George Chiang1, and
Gabriele V. Ronnett1, 2
Departments of 1 Neuroscience and
2 Neurology, The Johns Hopkins University School of
Medicine, Baltimore, Maryland 21205
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  -[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- 2 (TGF-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 µ), comparable to endogenous CO
production, significantly activated guanylyl cyclase, suggesting that
HO activity may regulate cGMP levels in the nervous system.
Key words:
heme;
metabolic turnover;
heme oxygenase;
carbon
monoxide;
guanylyl cyclase;
olfactory receptor neuron
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