The brain's NMDA receptor only opens when two conditions coincide
The NMDA receptor is a molecular gate that refuses to open on one signal alone. Glutamate must bind to it, and the neuron must already be electrically excited enough to eject a magnesium ion plugging the channel. That double lock makes it a coincidence detector, and a target for ketamine and alcohol.
Found in neurons, the receptor is one of three kinds of ion channel that respond to glutamate, alongside the AMPA and kainate types. It takes its name from N-methyl-D-aspartate, a synthetic molecule that binds to it and to no other glutamate receptor. Opening it needs glutamate plus a partner molecule, glycine or D-serine, but binding alone usually is not enough: a magnesium ion sits in the pore until the membrane is depolarised. Once both conditions are met, sodium, potassium and especially calcium flow through, and the incoming calcium switches on signalling pathways inside the cell.
Structurally it is a four-part assembly. Every working receptor carries two obligatory GluN1 subunits, combined with GluN2 subunits, of which there are four types, and sometimes inhibitory GluN3 subunits, of which there are two. GluN1 grabs glycine and GluN2 grabs glutamate. The GluN2B version has been tied to learning, memory and even feeding behaviour.
Many psychoactive substances block the channel, including PCP, alcohol and the cough suppressant dextromethorphan, and ketamine and nitrous oxide owe part of their anaesthetic and painkilling effects to it. Too much activity is dangerous: a flood of calcium can kill neurons through excitotoxicity, which is suspected in some neurodegenerative diseases. Yet blocking the receptor wholesale is no answer, because normal brain function depends on it, so a useful drug must damp only the excess. In 2002 Hilmar Bading's group showed that location matters: receptors at synapses support plasticity and neuroprotection, while those outside synapses drive death signals.
One drug story began by accident. In 1968 a woman taking amantadine for flu found her Parkinson's symptoms remarkably eased, launching interest in related compounds for brain disorders. Memantine, first made by Eli Lilly in 1963 as a failed attempt at a blood-sugar drug, was recognised in 1972 as potentially useful against neurodegeneration and from 1989 as a blocker of this receptor.
Source: NMDA receptor
