MODULATION BY CYCLIC-GMP OF THE ODOR SENSITIVITY OF VERTEBRATE OLFACTORY RECEPTOR-CELLS

Recent evidence has indicated a significant role for the cGMP second m essenger system in vertebrate olfactory transduction but no clear func tions have been identified for cGMP so far. Here, we have examined the effects of 8-Br-cGMP and carbon monoxide (GO) on odour responses of s alamander olfactory receptor neurons using perforated patch recordings . We report that 8-Br-cGMP strongly downregulates the odour sensitivit y of the cells, with a K1/2 of 460 nM. This adaptation-like effect can be mimicked by CO, an activator of soluble guanylyl cyclase, with a K 1/2 of 1 mu M. Sensitivity modulation is achieved through a regulatory chain of events in which cGMP stimulates a persistent background curr ent due to the activation of cyclic nucleotide-gated channels. This in turn leads to sustained Ca2+ entry providing a negative feedback sign al. One consequence of the Ca2+ entry is a shift to the right of the s timulus-response curve and a reduction in saturating odour currents. T ogether, these two effects can reduce the sensory generator current by up to twenty-fold. Thus, cGMP functions to control the gain of the G- protein coupled cAMP pathway. Another consequence of the action of cGM P is a marked prolongation of the odour response kinetics. The effects of CO/cGMP are long-lasting and can continue for minutes. Hence, we p ropose that cGMP helps to prevent saturation of the cell's response by adjusting the operational range of the cAMP cascade and contributes t o olfactory adaptation by decreasing the sensitivity of olfactory rece ptor cells to repeated odour stimuli.