Ryanodine receptors/calcium release channels (RyR) from rat brain cortex, show three different responses to cytoplasmic free calcium concentration: low, moderate and high Po, depending on the oxidation state of their SH residues (Marengo et al,1998). Therefore, RyR channels have been proposed as intracellular redox sensors. Neuronal RyR channels are most likely activated by an initial increase in cytoplasmic calcium concentration [calcium induced calcium release (CICR)]. We tested the calcium dependence of single RyR channels from rat brain cortex fused with planar lipid bilayers at different redox potentials or after treatment with NO donors. Exposure of the cytoplasmic face of the channel to different ratios of the redox pair GSH/GSSG, modified the degree of channel activation, measured as fractional open time (Po). In the presence of a ratio GSH/GSSG=40/1 (redox potential=-220 mV), all RyR channels displayed the low Po behaviour. After changing the redox potential from -220 to -180 mV, the channels displayed the moderate Po response, increasing Po at all [Ca²⁺] tested (0.1 to 500 μM). This effect was maximal at activating cytoplasmic [Ca2+]: Po increased from 0.036 ± 0.003 to 0.390 ± 0.111 (mean ± S.E.M.) at 14 μM [Ca²⁺] (n=10). The calcium dependence of channel activity changed due to a tenfold increase in apparent affinity for activation by calcium (Ka = 110 ± 18 μM at -220 mV; Ka=12 ± 2 μM at -180 mV) and a fivefold decrease in apparent affinity for inhibition by calcium (Ki=5 ± 1 μM at -220 mV; Ki=24 ± 4 μM at -180 mV). Exposure of low Po channels to the NO donor SNAP (15 μM) induced a fivefold increase in Po at 14 μM cytoplasmic [Ca²⁺] (n=13). The channel switched to the moderate Po behaviour due to an increase in apparent affinity for activation by calcium (Ka=189 ± 30 μM, control; Ka=39 ± 5 μM, SNAP) and a decrease in apparent affinity for inhibition by calcium (Ki=12 ± 2 μM, control; Ki=35 ± 5 μM, SNAP). Exposure of low Po channels to the NO donor GSNO (200 μM) induced a fourfold increase in Po at 100 μM cytoplasmic [Ca²⁺] (n=13). The channel switched to the moderate Po behaviour due to an increase in apparent affinity for activation by calcium (Ka=141 ± 29 μM, control; Ka=60 ± 18 μM, GSNO) and a decrease in apparent affinity for inhibition by calcium (Ki=8 ± 0.07 μM, control; Ki=20 ± 5 μM, GSNO). Our results suggest that SH oxidation and the modification induced by NO donors of RyR channels favours amplification of calcium signalling via CICR, and may therefore participate in a diversity of neuronal processes like neurotransmission and synaptic plasticity.