T. Ingi et Gv. Ronnett, DIRECT DEMONSTRATION OF A PHYSIOLOGICAL-ROLE FOR CARBON-MONOXIDE IN OLFACTORY RECEPTOR NEURONS, The Journal of neuroscience, 15(12), 1995, pp. 8214-8222
Recent evidence suggests that, like nitric oxide (NO), carbon monoxide
(CO), another activator of soluble guanylyl cyclase, may serve as an
intercellular messenger in the brain. Heme oxygenase, which converts h
eme to biliverdin and CO, is abundantly expressed in the brain and is
localized to discrete neuronal populations. However, evidence for the
actual generation of CO by neurons is lacking. Heme oxygenase-a immuno
reactivity is abundantly present in olfactory receptor neurons where i
t essentially colocalizes with immunoreactivity to soluble guanylyl cy
clase, the target of CO action. To examine the generation of CO by neu
rons, we measured CO production directly and determined its relationsh
ip to cyclic GMP levels in cultured rat olfactory receptor neurons. Th
is system has the advantage of not having measurable NO production, wh
ich could confound results since NO is a more potent activator of guan
ylyl cyclase than CO. Metabolic labeling experiments permitted the dir
ect measurement of (CO)-C-14 production by neurons in vitro. CO releas
e parallels endogenous cyclic GMP concentrations with its peak at the
immature stage of neuronal differentiation in culture. Cyclic GMP prod
uction is inhibited by zinc protoporphyrin-g and zinc deuteroporphyrin
IX 2,4-bis glycol, inhibitors of heme oxygenase, indicating that CO i
s an endogenous regulator of soluble guanylyl cyclase activities in th
ese cells. Transforming growth factor-beta 2, an olfactory neurogenic
factor, specifically shows a negative effect on CO release in olfactor
y receptor neurons. These results indicate that CO may serve as a gase
ous neuronal messenger linked to cyclic GMP production and suggests it
s involvement in developmental processes of the olfactory receptor neu
ron.