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Vol. 286, Issue 1, 99-109, July 1998
Department of Pharmacology, College of Veterinary Medicine, Cornell
University, Ithaca, New York
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 µM) in a rapidly reversible and dose-dependent
manner. IC50 values were estimated at ~150 µM cGMP for
25 µM kainate and ~500 µM cGMP for 100 µM 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.
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