Group S8A serine proteases, including a novel enzyme cadeprin, induce long-lasting, metabotropic glutamate receptor-dependent synaptic depression in rat hippocampal slices.
Long-term potentiation and long-term depression (LTD) are forms of synaptic plasticity in the central nervous system. We now report that a group of chymotrypsin-like serine proteases, especially members of the S8A subfamily, induce LTD of evoked potentials in rat hippocampal slices. The proteolytic activity of these enzymes is required for the induction of LTD, as serine protease inhibitors prevent the effect. The depression is partly mediated by the suppression of transmitter release from glutamatergic terminals but also involves an elevation of action potential threshold with no change of post-synaptic membrane potential or input resistance. We have also isolated a novel and more potent related enzyme, cadeprin, from Aspergillus. The LTD produced by all of these proteases is not dependent on receptors for several transmitter systems, including N-methyl-d-aspartate or adenosine receptors, but is prevented by blocking group I metabotropic glutamate receptors. The activity of cadeprin, subtilisin and other S8A serine proteases may shed light on the mechanisms of LTD and a related endogenous molecule could have a physiological or pathological role as a modulator of synaptic plasticity in the mammalian hippocampus.
MacGregor
Duncan G
DG
Institute of Biomedical and Life Sciences, West Medical Building, University of Glasgow, Scotland, UK.
Mallon
Andrew P
AP
Harvey
Alan L
AL
Young
Louise
L
Nimmo
Hugh G
HG
Stone
Trevor W
TW
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D008297:Male; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000494:pharmacology*
D001578:Benzopyrans; D004791:Enzyme Inhibitors; C442478:N-phenyl-7-(hydroxyimino)cyclopropa(b)chromen-1a-carboxamide; D018094:Receptors, Metabotropic Glutamate; D012697:Serine Endopeptidases; C526006:cadeprin