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The drug ketamine is used for medicinal purposes and also, because of its hallucinatory effects, used recreationally.  Ketamine is classified as an NMDA receptor antagonist. When a neuron is stimulated, glutamate is released into the synapse and then binds to the NMDA receptor.  This triggers the opening of the ion channel.  However in the ionotropic pore there are magnesium ions, which greatly limits the ion flow. To counter this the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor also binds glutamate and flows freely.  A voltage is built up by the flowing of sodium and potassium ions that eventually expels the magnesium, allowing for both sodium and calium ions to pass through.  When ketamine binds to the NMDA receptor, the ion channel becomes plugged whether or not the magnesium is expelled, in particular blocking the flow of calcium.  This means more AMPA receptors would be created, as well as Kainate receptors, which are also glutamate receptors that are not open as long.  This effect has been known to cause problems with memory.  In fact katamine and PCP, another NMDA receptor antagonist drug, were used to model the hypoglutamate state of schizophrenia.  Today, ketamine is primarily used as a general anesthetic, but is also used as an analgesic and a bronchodilator to help breathing.  It has even been proven effective in decreasing depression symptoms that accompany bipolar disorder. In knowing in greater detail the structure and function of both ketamine and the NMDA receptor, we can better understand the effects of ketamine and other similar drugs on the body both short and long term.

 

The NMDA Receptor primarily functions as a specific type of glutamate receptor. In addition to binding NMDA, its namesake, the receptor also contains binding sites for a wide variety of other molecules, most notably Benzodiazepines, D-serine, and Glycine. These binding sites occur extracellularly along the ligand binding domain (LBD). Glutamate binding alone is not enough to trigger a conformational change. In order to open the ion-channel, the NMDA receptor makes use of either Glycine or D-Serine, which are co-agonists. These two molecules comptete for the same binding site, and only their binding in conjunction with Glutamate can alter the protein's shape to expose the ion-channel. Furthermore, this allows the Mg2+ plug to be ejected from the pore during cellular depolarization-- the final stage before ion transport can begin.

Molecules such as Phencyclidine (PCP), Ketamine, and dizocilpine (MK-801) are known to block the flow of ions through the NMDA receptor. These molecules are non-competitive antagonists because they do not interfere with either the Glutamate or Glycine/D-Serine active sites. Instead, they bind to the ion-channel, similarly to magnesium. Given that the crystal structure of the ion-channel binding site has not yet been proven, it is difficult to pin down the roles of each residue in channel-blockage binding. However, there is evidence that the ideal binding site for these molecules occurs along side-chain oxygens of Asn 0 Residues, Phe and Leu at -1, Met +25, Val +28, and Ala +29. The pore itself is about 5.5 Angstroms in diameter which suggests the vast majority of blockers bind at the entrance to this very narrow section.

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