Journal of Physiology (1997) 504.P Ifenprodil selectively reduces the open probability of high conductance NMDA channels in dentate gyrus granule cells from 0-day-old rats Juan Pifia-Crespo and Alasdair J. Gibb Department of Pharmacology, University College London, London WC1E 6BT We have shown, based on the analysis of s channels, that dentate gyrus granule cells exl receptors with different unitary conductance (Pifia-Crespo & Gibb, 1996). In this study we I sensitivity of both channel species to ifenprod subunit-selective NMDA receptor antagonisl 1993). Patch-clamp techniques were used to r channel events induced by glutamate (50-100 n (5/#M) and glycine (10/M) in outside-out pat from dentate gyrus granule cells in hippoc obtained from decapitated 0-day-old rats. Hist fitted using the maximum likelihood method (4 Sigworth, 1995). Ifenprodil had no effect on conductance of both NMDA channel species, bu a marked reduction in the open probabil conductance NMDA channels (Fig. 1). A 250 40 pS 200 47 pS 150 O? . A pS ..,. U_ 100 l8p 50- 0: 0 1 2 3 Amplitude (pA) B 250 200 o 150 C 0~ ,, 1 00 50 0 40 pS 18 pS 47 pS 0 1 2 3 Amplitude (pA) ,ingle NMDA press NMDA and kinetics looked at the [il, a NR2B- t (Williams, ecord single- IM) or NMDA tches excised ampal slices ;ograms were Colquhoun & the unitary it it produced These results support the hypothesis that in P0 dentate gyrus granule cells, high conductance NMDA channels probably arise from NMDA channels containing the NMDA receptor subunit NR2B. Supported by the MRC, the Royal Society and the Nuffield Foundation. J.P.-C. is supported by a Venezuelan CONICIT-Univ. Centroce. L.A. scholarship. REFERENCES Colquhoun, D. & Sigworth, F.J. (1995). In Single Channel Recording, ed. Sakmann, B. & Neher, E., pp. 483-587. Plenum Press, New York. Piiia-Crespo, J.C. & Gibb, A.J. (1996). J Physiol. 493.P, 48P Williams, K. (1993). Mol. Pharmacol. 44, 851-859. Dual effect of memantine on NMDA channels in acutely isolated rat hippocampal neurones S. Koshelev, A. Sobolevsky and B. Khodorov Institute of General Pathology and Pathophysiology, Baltiyskaya 8, 125315 Moscow, Russia ity of high It has been shown previously (Sobolevsky et al. 1996) in isolated hippocampal neurones that the 'trapping blocker' of open agonist-activated NMDA channels, memantine (MEM), is also able to block the channels without agonist assistance (unliganded channels). Cells were isolated (Vorobiev, 1991) from neonatal rats that had been killed by decapitation. In the present work it has been revealed that the blockade of unliganded NMDA channels by MEM can be accelerated by glycine (10 uM), while unblocking of these channels is practically glycine insensitive. The aspartate (ASP)-induced response following 1 min MEM application (Fig. 1A) consisted of two components: (i) the fast peak response followed by (ii) a slow current increase. The latter reflected the unblocking (untrapping) of the channels. The peak component of the current (Ip - Ib) could be abolished by a 10 s washout of the cell with the control solution (Fig. 1B), while the slow component (Ib) remained practically unchanged. Reapplication of MEM for 10 s restored the ability of NMDA channels to produce the peak response to a new ASP application (not illustrated). Analysis of the concentration-, time-, voltage- and pH-dependencies of these effects led us to hypothesize that along with the blockade of open channels (via site 1), MEM is also able to modulate the activation of the unliganded channels (via site 2) by increasing the probability of their spontaneous and agonist-induced openings. 4 5 Fig. 1. Distribution of single NMDA channel current amplitudes in control conditions (A) and after application of 10 uM ifenprodil (B). 52P View publication stats View publication stats