Glycine receptor in hippocampal neurons as a target for action of extracellular cyclic nucleotides

Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are well known intracellular second messengers. At present study, we describe the effects of extracellularly applied cAMP and cGMP on glycine-induced chloride currents (IGly) in isolated rat hippocampal pyramidal neurons. 50 or 500 μM glycine was applied for 600 ms with 1 min intervals. cAMP and cGMP were co-applied with glycine. We found that both cAMP and cGMP rapidly, reversibly and in a dose-dependent manner accelerated the IGly desensitization. The effect was more prominent on IGly induced by 500 μM than by 50 μM glycine. Dose-response curves were constructed in the 0.1-100,000 nM range of cAMP and cGMP concentrations. They demonstrate that threshold concentration of both compounds was about 1 nM and maximal effect was manifested at 100 nM. When cAMP and cGMP were added to the recording pipette, their extracellular application caused the effects similar to those obtained with normal intracellular medium. The effects of cyclic nucleotides remained unchanged in the presence of the antagonist of adenosine receptors in extracellular solution, and the agonist of adenosine receptors did not mimic the effect of cyclic nucleotides. The changes in the decay kinetics were equally pronounced at negative and positive membrane potentials. When co-administered 1 nM cAMP and 1 nM cGMP caused a weaker effect than either of the compounds alone which suggests a negative interaction between binding sites for cAMP and cGMP. This work describes a novel mode of action of cyclic nucleotides, namely, the modulation of GlyRs functions from extracellular side.