REGULATION OF CYCLIC NUCLEOTIDE-GATED CHANNELS AND MEMBRANE EXCITABILITY IN OLFACTORY RECEPTOR-CELLS BY CARBON-MONOXIDE

1. The effect of the putative neural messenger carbon monoxide (CO) an d the role of the cGMP second-messenger system for olfactory signal ge neration was examined in isolated olfactory receptor neurons (ORNs) of the tiger salamander. 2. With the use of whole cell voltage-clamp rec ordings in combination with a series of ionic and pharmological tests, it is demonstrated that exogenously applied CO is a potent activator (K-1/2 = 2.9 mu M) of cyclic nucleotide-gated (CNG) channels pre vious ly described to mediate odor transduction. 3. Several lines of evidenc e suggest that CO mediates its effect through stimulation of a soluble guanylyl cyclase (sGC) leading to formation of the second-messenger c GMP. This conclusion is based on the findings that CO responses show a n absolute requirement for guanosine 5'-triphosphate (GTP) in the inte rnal solution, that no direct effect of CO on CNG currents in the abse nce of GTP is detectable, and that a blocker of sGC activation, LY8538 3 (10 mu M), completely inhibits the CO response. 4. The dose-response curve for cGMP at CNG channels is used as a calibration to provide a quantitative estimate of the CO-stimulated cGMP formation. This analys is implies that CO is a potent activator of olfactory sGC. 5. Perforat ed patch recordings using amphotericin B demonstrate that low micromol ar doses of CO effectively depolarize the membrane potential of ORNs t hrough tonic activation of CNG channels. This effect in turn regulates excitable and adaptive properties of ORNs and modulates neuronal resp onsiveness. 6. These data argue for an important role of the cGMP path way in olfactory signaling and support the idea that CO may function a s a diffusible messenger in the olfactory system.