IDENTIFICATION OF A LONG-LASTING FORM OF ODOR ADAPTATION THAT DEPENDSON THE CARBON-MONOXIDE CGMP 2ND-MESSENGER SYSTEM

The diffusible messenger carbon monoxide (CO) has been proposed to med iate endogenous cyclic guanosine 3',5'-monophosphate (cGMP) formation and sensory adaptation in vertebrate olfactory receptor neurons (ORNs) . We have identified and characterized a long-lasting form of odor res ponse adaptation (LLA) that operates at the level of isolated salamand er ORNs and does not require any interactions from other cells. Manife stations of LLA are seen in reduced amplitude and prolonged kinetics o f the cAMP-mediated excitatory odor response and the generation of a p ersistent current component that lasts for several minutes and is attr ibutable to cyclic nucleotide-gated (CNG) channel activation by cGMP. Because these effects can be mimicked by micromolar amounts of exogeno us cGMP or CO, we applied various inhibitors of cGMP formation. LLA is abolished selectively by heme oxygenase inhibitors known to prevent C O release and cGMP formation in ORNs, whereas odor excitation remains unaffected. In contrast, blockers of nitric oxide synthase are unable to eliminate LLA. Several controls rule out a contribution of nonspeci fic actions to the effects of CO inhibitors. The results indicate that endogenous CO/cGMP signals contribute to olfactory adaptation and und erlie the control of gain and sensitivity of odor transduction. The fi ndings offer a mechanism by which a single, brief odor stimulus can be translated into long-lasting intracellular changes that could play an important role in the perceptual adaptation to odors, and explain the longstanding puzzle that the olfactory CNG channels can be gated by b oth cAMP and cGMP.