Summary
We have studied the effects of calphostin C, an antagonist of the regulatory subunit of protein kinase C, on the induction and expression of long-term potentiation (LTP) and on responses mediated by activation of N-methyl-d-aspartate (NMDA) receptors in rat hippocampal slices. No effect of calphostin C was observed on preestablished LTP, even at concentrations of 2–3 μmol/l. In contrast, the drug was found to prevent LTP induction. This effect was concentration-dependent, although high concentrations were needed (1–2 μmol/l), and, at the lower concentrations, it could be partially antagonized by using coactivation of two pathways instead of single input activation. While calphostin C did not alter synaptic transmission mediated by activation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, it considerably interfered with the function of NMDA receptors. The drug blocked the NMDA receptor-mediated component of burst responses, significantly antagonized the NMDA receptor-mediated synaptic responses recorded in the presence of an AMPA receptor antagonist, and blocked the effect of iontophoretic application of NMDA on regular synaptic transmission. These results are consistent with the idea that calphostin C prevents the induction of long-term potentiation by interfering with the function of NMDA receptors.
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References
Akers RF, Lovinger DM, Colley PA, Linden DJ, Routtenberg A (1986) Translocation of protein kinase C activity may mediate hippocampal long-term potentiation. Science 231:587–589
Amador M, Dani JA (1991) Protein kinase inhibitor, H-7, directly affects N-methyl-d-aspartate receptor channels. Neurosci Lett 124:251–255
Aniksztejn L, Otani S, Ben-Ari Y (1992) Quisqualate metabotropic receptors modulate NMDA currents and facilitate induction of long-term potentiation through protein kinase C. Eur J Neurosci 4:500–505
Bliss TVP, Gardner-Medwin AR (1973) Long-lasting potentiation of synaptic transmission in hippocampal slices. J Physiol (Lond) 232:357–374
Bruns RF, Miller FD, Merriman RL, Howbert JJ, Heath WF, Kobayashi E, Takahashi I, Tamaoki T, Nakano H (1991) Inhibition of protein kinase C by calphostin C is light-dependent. Biochem Biophys Res Commun 176:288–293
Chen L, Huang L-YM (1992) Protein kinase C reduces Mg2+ block of NMDA receptor channels as a mechanism of modulation. Nature 356:521–523
Denny JB, Polan-Curtain J, Rodriguez S, Wayner MJ, Armstrong DL (1990) Evidence that protein kinase M does not maintain long-term potentiation. Brain Res 534:201–208
Huang Y-Y, Colley PA, Routtenberg A (1992) Postsynaptic then presynaptic protein kinase C activity may be necessary for long-term potentiation. Neuroscience 49:819–827
Kauer JA, Malenka RC, Nicoll RA (1988) NMDA application potentiates synaptic transmission in the hippocampus. Nature 334: 250–252
Kelso SR, Nelson TE, Leonard JP (1992) Protein kinase C-mediated enhancement of NMDA currents by metabotropic glutamate receptors in Xenopus oocytes. J Physiol (Lond) 449:705–718
Klann E, Chen S-J, Sweatt JD (1991) Persistent protein kinase activation in the maintenance phase of long-term potentiation. J Biol Chem 266:24253–24256
Kobayashi E, Nakano H, Morimoto M, Tamaoki T (1989) Calphostin C (UCN-1028C), a novel microbial compound, is a potent and specific inhibitor of protein kinase C. Biochem Biophys Res Commun 159:548–553
Larson J, Lynch G (1986) Induction of synaptic potentiation in hippocampus by patterned stimulation involves two events. Science 232:985–988
Leahy JC, Vallano ML (1991) Differential effects of isoquinolinesulfonamide protein kinase inhibitors on CA1 responses in hippocampal slices. Neuroscience 44:361–370
Levinger DM, Wong KL, Murakami K, Routtenberg A (1987) Protein kinase C inhibitors eliminate hippocampal long-term potentiation. Brain Res 436:177–183
Lynch G, Larson J, Kelso S, Barrionuevo G, Schottler F (1983) Intracellular injections of EGTA block induction of hippocampal long-term potentiation. Nature 305:719–721
Malenka RC, Kauer JA, Zucker RJ, Nicoll RA (1988) Postsynaptic calcium is sufficient for potentiation of hippocampal synaptic transmission. Science 242:81–84
Malenka RC (1991) Postsynaptic factors control the duration of synaptic enhancement in area CA1 of the hippocampus. Neuron 6:53–60
Malenka RC, Lancaster B, Zucker RS (1992) Temporal limits on the rise in postsynaptic calcium required for the induction of long-term potentiation. Neuron 9:121–128
Malinow R, Madison DV, Tsien RW (1988) Persistent protein kinase activity underlying long-term potentiation. Nature 335:820–824
Muller D, Lynch G (1988a) N-methyl-d-aspartate receptor mediated component of synaptic responses to single pulse stimulation in rat hippocampal slices. Synapse 2:666–668
Muller D, Lynch G (1988b) Long-term potentiation differentially affects two components of synaptic responses in hippocampus. Proc Natl Acad Sci USA 85:9346–9350
Muller D, Buchs P-A, Dunant Y, Lynch G (1990) Protein kinase C activity is not responsible for the expression of long-term potentiation in hippocampus. Proc Natl Acad Sci USA 87:4073–4077
Muller D, Bittar P, Boddeke H (1992) Induction of stable long-term potentiation in the presence of the protein kinase C antagonist staurosporine. Neurosci Lett 135:18–22
Reymann KG, Davies SN, Matthies H, Kase H, Collingridge GL (1990) Activation of a K-252b-sensitive protein kinase is necessary for a post-synaptic phase of long-term potentiation in area CA1 of rat hippocampus. Eur J Neurosci 2:481–486
Reymann KG, Frey U, Jork R, Matthies H (1988) Polymyxin B, an inhibitor of protein kinase C, prevents the maintenance of synaptic long-term potentiation in hippocampal CA1neurons. Brain Res 440: 305–314
Wang J, Feng D-P (1992) Postsynaptic protein kinase C essential to induction and maintenance of long-term potentiation in the hippocampal CA1region. Proc Natl Acad Sci USA 89:2576–2580
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Lopez-Molina, L., Boddeke, H. & Muller, D. Blockade of long-term potentiation and of NMDA receptors by the protein kinase C antagonist calphostin C. Naunyn-Schmiedeberg's Arch Pharmacol 348, 1–6 (1993). https://doi.org/10.1007/BF00168529
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DOI: https://doi.org/10.1007/BF00168529