Role of muscarinic receptors, G-proteins, and intracellular messengers in muscarinic modulation of NMDA receptor-mediated synaptic transmission

Previously, we reported that activation of muscarinic receptors modulates N -methyl-D-aspartate (NMDA) receptor-mediated synaptic transmission in audit ory neocortex [Aramakis et al. (1997a) Exp Brain Res 113:484-496]. Here, we describe the muscarinic subtypes responsible for these modulatory effects, and a role for G-proteins and intracellular messengers; The muscarinic ago nist oxotremorine-M (oxo-M), at 25-100 mu M, produced a long-lasting enhanc ement of NMDA-induced membrane depolarizations. We examined the postsynapti c G-protein dependence of the modulatory effects of oxo-M with the use of t he G-protein activator GTP gamma S and the nonhydrolyzable GDP analog GDP b eta S. Intracellular infusion of GTP gamma S mimicked the facilitating acti ons of oxo-M. After obtaining the whole-cell recording configuration, there was a gradual, time-dependent increase of the NMDA receptor-mediated slow- EPSP, and of iontophoretic NMDA-induced membrane depolarizations. In contra st, intracellular infusion of either GDP beta S or the IP3 receptor antagon ist heparin prevented oxo-M mediated enhancement of NMDA depolarizations. T he muscarinic receptor involved in enhancement of NMDA iontophoretic respon ses is likely the M-1 receptor, because the increase was prevented by piren zepine, but not the M-2 antagonists methoctramine or AF-DX 116. Oxo-M also reduced the amplitude of the pharmacologically isolated slow-EPSP, and this effect was blocked by M-2 antagonists. Thus, muscarinic-mediated enhanceme nt of NMDA responses involves activation of M1 receptors, leading to the en gagement of a postsynaptic G-protein and subsequent IP3 receptor activity S ynapse 32:262-275, 1999. (C) 1999 Wiley-Liss,Inc.