DIRECT DEMONSTRATION OF A PHYSIOLOGICAL-ROLE FOR CARBON-MONOXIDE IN OLFACTORY RECEPTOR NEURONS

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.