The NMDA Receptor as the Ultimate Target of Anesthetic Action

It was discovered later that ketamine and phen-cyclidine act as noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor. This receptor (figure 16.1) is unique in several respects. The opening probability of the receptor-associated ion channel is both voltage- and transmitter-dependent. It opens under two conditions. First, the presynapse must release the transmitter glutamate and, second, the post-synaptic membrane must be depolarized to about —35 mV. When the membrane potential assumes a value nearly equivalent to the resting potential, the channel will be blocked by a magnesium ion that binds in a voltage-dependent manner to a site in the lumen of the channel. This blockade will be removed if the membrane is depolarized. The receptor-operated channel is permeable to Na+, K+, and Ca2+. The permeation of Ca2+ through the open NMDA channel triggers a number of biochemical changes inside the postsynaptic terminal that modify the strength of the synapse. Ca2+ activates the enzyme nitric oxide synthase (NOS) that catalyzes the production of nitric oxide (NO). NO, a gas that rapidly diffuses through the cell membrane, acts as a retrograde messenger and induces rapid and transient changes in both presynaptic transmitter release and postsynaptic sensitivity to the released transmitter. In addition, Ca2+ triggers posttranslational changes of neuronal proteins and changes in protein synthesis that are responsible for persistent modifications of synaptic strength.

The NMDA receptor channel complex is a potential target for many different drugs:

1. The receptor-associated ion channel contains a binding site (PCP receptor) for noncompetitive antagonists, to which ketamine and phencycli-dine belong. These antagonists block the influx of Na+ and Ca2+ ions and thereby antagonize (1) the depolarization of the postsynaptic membrane induced by the agonist glutamate and (2) the induction of plastic changes by Ca2+.

2. The recognition site for the endogenous agonist glutamate can be blocked by specific competitive NMDA antagonists.

3. A strychnine-insensitive glycine binding site, the coactivation of which is necessary for receptor activation, can be blocked by glycine antagonists.

4. A binding site for polyamines can be blocked by polyamine antagonists.

5. The enzyme NOS can be inactivated by various NOS inhibitors.

Ketamine and phencyclidine bind to the PCP receptor and block the influx of Ca2+ and Na+. Like most noncompetitive NMDA antagonists, they are not fully selective but also interact with other components of the CNS. But these side effects are not able to fully account for the drugs' anesthetic and psychotomimetic properties. It


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