BLOCK OF CYCLIC NUCLEOTIDE-GATED CHANNELS IN SALAMANDER OLFACTORY RECEPTOR NEURONS BY THE GUANYLYL CYCLASE INHIBITOR LY83583

1. Using whole cell voltage-clamp recordings, the guanylyl cyclase inh ibitor LY83583 [6-(phenylamino)-5,8-quinolinedione] is shown to act as a potent blocker of cyclic nucleotide-gated (CNG) channels in isolate d olfactory receptor neurons (ORNs) of the tiger salamander. 2. Under our experimental conditions, onset of the blockade by LY83583 occurs o n the time scale of seconds and is completely reversed upon wash-out o f the drug. Dose-response curves reveal a K-d of 1.4 mu M (at -60 mV). Other data suggest that LY83583 acts within the CNG channel pore and that the channels must be in an activated state before the drug can ex ert its effect. 3. It appears that LY83583 can act on both CNG channel s and soluble guanylyl cyclase (sGC) and that these two effects can be distinguished by their different recovery behaviors. The LY83583-indu ced blockade of CNG channels activated directly by guanosine 3',5' cyc lic monophosphate (cGMP) is rapidly reversible (with a recovery time c onstant of approximate to 3 s) whereas previous results have shown tha t no recovery is obtained during minute-long washing periods when the channels are activated indirectly through exogenous carbon monoxide ap plication, which acts as a stimulator of sGC in ORNs. 4. LY83583 appea rs to be a novel and useful agent in examining neural functions due to CNG channel responses.