FIGURE 23 Features of non-NMDA and NMDA glutamate receptors. (A) Non-NMDA receptors: (A1) In the absence of agonist, the channel is closed; (A2) glutamate binding leads to channel opening and an increase in Na+ and K+ permeability, which depolarizes the cell to produce an EPSP. (B) NMDA: (B2) The presence of agonist leads to a conformational change and channel opening, but no ionic flux occurs because the pore of the channel is blocked by Mg2+; (B3)

block is removed and the agonist-induced opening of the channel leads to changes in ion flux (including Ca2+ influx into the cell).

of glutamate binding, a channel opens that is highly permeable to both Na+ and K+ (Fig. 23A). The agent a-amino-3-hydroxy-5-methylisoxazol-4-propinoic acid (AMPA) is a specific agonist of non-NMDA receptors. Inhibitors of non-NMDA receptors include the quinoxaline derivatives 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 1,2,3,4-tetrahydro-6-nitro-2,3,-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX).

The NMDA glutamate receptors differ from non-NMDA receptors in four ways. First, they are selectively blocked by the agent 2-amino-5-phosphonovalerate (APV). Second, they have a high permeability to Ca2+ as well as Na+ and K+. Third, at normal values of the resting potential, the pore of the channel is blocked by Mg2+. Thus, even if glutamate binds to the receptor, there will be no ionic flow (and no EPSP) because the channel is blocked. The block can be relieved by depolarization, which presumably displaces the Mg2+ from the pore (Fig. 23B). A fourth and final difference between non-NMDA and NMDA channels is a glycine-binding site on the NMDA channel. Glycine must be present for NMDA receptors to function. The physiologic role of this binding in regulating the channel is unclear, however. Basal levels of glycine in the vicinity of cells with NMDA receptors seem to be sufficiently high to maintain function of the NMDA receptor. Several of these unique features of the NMDA channel have important physiologic consequences. First, activation of the NMDA receptor results in more than a simple EPSP. The influx of calcium associated with the channel opening can induce a cascade of biochemical reactions, including activation of Ca2+-dependent phosphatases, kinases, and proteases. Second, the dual regulation of the channel by glutamate and voltage (depolarization) allows other synaptic inputs through electrotonic propagation and spatial summation to profoundly regulate the ability of an NMDA-mediated synaptic input to affect a postsynaptic cell.

Slow Synaptic Potentials Produced by Metabotropic Receptors

A common feature of the types of synaptic actions described above is the direct binding of the transmitter with the receptor-channel complex. An entirely separate class of synaptic actions is due to the indirect coupling of the receptor with the channel. So far, two types of coupling mechanisms have been identified. These include a coupling of the receptor and channel through an intermediate regulatory protein or coupling through a diffusible second messenger system. Receptors that activate the latter mechanism are called metabotropic, because they involve changes in the metabolism of second messengers or other compounds such as ATP and phospolipids. Because they are the most common, attention will be focused on the responses mediated by metabotropic receptors.

A comparison of the features of direct, fast iono-tropic- and indirect, slow metabotropic-mediated synap-tic potentials is shown in Fig. 24. Slow synaptic

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