Protein phosphatase inhibitors facilitate DHPG-induced LTD in the CA1 region of the hippocampus.
We have shown earlier that activation of metabotropic glutamate (mGlu) receptors using a group I-specific mGlu receptor agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG), can induce long-term depression (LTD) in the CA1 region of the hippocampus. In an attempt to determine the signal transduction mechanisms involved in this form of synaptic plasticity, we have tested the effects of a range of inhibitors on DHPG-induced LTD. In vitro grease-gap electrophysiological recordings were performed in the rat hippocampal CA1 region. We have found that DHPG-induced LTD is resistant to the two potent protein kinase C (PKC) inhibitors, Gö 6976 (10 microM) and Gö 6983 (10 microM), the potent and selective protein kinase A (PKA) inhibitor, KT 5720 (10 microM), and the potent broad spectrum kinase inhibitor, staurosporine (10 microM). In contrast, non-selective inhibitors of protein phosphatases (PP1 and PP2A), okadaic acid (1 microM) or calyculin A (1 microM), facilitated DHPG-induced LTD. However, an inhibitor of protein phosphatase 2B, FK 506 (1 microM), did not influence this process. The PP1/PP2A protein phosphatase inhibitors, but none of the other agents tested, also inhibited (S)-alpha-methyl-4-carboxyphenylglycine (MCPG)-induced reversal of DHPG-induced LTD. These data suggest that activation of neither PKC nor PKA is involved in DHPG-induced LTD. They do, however, suggest that the process is under regulation by protein phosphorylation and dephosphorylation.
MRC Centre for Synaptic Plasticity, Department of Anatomy, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK.
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Schnabel
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Kilpatrick
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Collingridge
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011493:Protein Kinase C / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D019319:Okadaic Acid; D008734:Methoxyhydroxyphenylglycol; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases; C010117:3,4-dihydroxyphenylglycol