Extracellular 3',5' cyclic guanosine monophosphate inhibits kainate-activated responses in cultured mouse cerebellar neurons.

The effects of extracellularly applied 3'-5' cyclic guanosine monophosphate (cGMP) on kainate responses from cultured cerebellar granule and Purkinje neurons were investigated using whole-cell and outside-out patch recording modes. Cerebellar granule cell responses to kainate were not homogeneous, nor were the effects of cGMP. Therefore, effects of cGMP are described for two groups of granule cells categorized on the basis of the underlying channel conductance estimated by variance analysis. Cells with high-noise kainate responses had average channel conductances of 5 to 7 picoseimens, whereas the average conductances of low-variance noise responses were 0.3 to 2.0 picoseimens. High-noise kainate responses were inhibited by externally applied cGMP (5-1000 microM) in a rapidly reversible and dose-dependent manner. IC50 values were estimated at approximately 150 microM cGMP for 25 microM kainate and approximately 500 microM cGMP for 100 microM kainate. Evidence that cGMP-mediated inhibition of high-noise kainate responses occurred by a competitive mechanism included the following: 1) cGMP-mediated inhibition was overcome by increasing agonist concentration. 2) The shape of kainate current-voltage (I-V) curves and their reversal potentials were unchanged in cGMP. 3) Neither the estimated conductance nor the kinetics of the kainate-activated channels was affected by cGMP. In contrast to the uniform effects of cGMP on the high-noise kainate responses, the effects on low-noise kainate responses were variable. Half of the low-noise kainate responses were inhibited by cGMP to a similar extent as the high-noise responses; however, the other 50% of cells exhibiting low-noise kainate responses appeared to be less sensitive to the cyclic nucleotide. Moreover, cGMP coapplication decreased the estimated conductances for some low-noise kainate responses and altered their noise kinetics, which suggests either that cGMP-sensitive and -insensitive kainate receptor channels are coexpressed in these cells or that cGMP-mediated inhibition is not competitive for this subgroup of glutamate receptor channels. Overall, these data indicate that there are direct inhibitory effects of extracellular cGMP on a large group of excitatory synapses in the CNS--effects that need to be taken into account when investigators utilize membrane-permeable cGMP analogs. Whether this cGMP-mediated inhibition has a functional role in brain is unknown.