NMDA receptor up-regulates pyroglutamyl peptidase II activity in the rat hippocampus

Ecto-peptidases hydrolyze peptides in the extracellular fluid of the brain. This process is critical for defining the strength of peptidergic communication. A few studies suggest that brain ecto-peptidase activities are regulated by brain function but the extracellular messengers involved are generally unknown. Pyroglutamyl peptidase II (PPII) is specific for thyrotropin releasing hormone (TRH), a tripeptide with multiple homeostatic functions in brain. The purpose of this study was to identify regulators of brain PPII activity. Electrical stimulation (multiple tetani) did not change PPII activity in cortical or hippocampal slices. However, in hippocampal slices, blockade of calcium channels with high magnesium, or of L-type calcium channels (LTCC) or NMDA receptors, decreased PPII activity, while blockade of AMPA or GABAA receptors did not. Blockade of NMDA receptors did not change PPII mRNA levels but decreased PPII levels. The activity of another ecto-peptidase, aminopeptidase N, was also down regulated by a magnesium blockade, not regulated by NMDA receptor blockade and increased by LTCC blockade. The data show a differential regulation of the activity of ecto-peptidases by that of Ca2+ channel and that synaptic activity, through the NMDA receptor, specifically regulates that of pyroglutamyl peptidase II.