Scientists have now learned more about a critical protein in the brain called the NMDA receptor, tracking every atom as brain signals are transmitted through it. The receptor can be found at synapses, where neurons meet and release neurotransmitters. The NMDA or N-Methyl-D-Aspartate receptor, for example, is responsive to the neurotransmitter glutamate. Using cryo-electron microscopy, scientists have unlocked the details of how it opens and shuts. The findings have been reported in Cell.
The NMDA receptor sits in the membrane of neuronal cells; its channel spans the membrane and it has a binding section that protrudes from the cell. When glycine and glutamic acid bind to the receptor, it rocks, and small filaments pull on a gate that opens the channel. When a receptor antagonist binds to the receptor, it gets rocked in another way, the filaments come loose, and the gate closes. These mechanistic insights may help us learn more about diseases that involve the brain and the NMDA receptor, including epilepsy, depression, stroke, or schizophrenia.
"This is all happening because the subunit arrangement changes quite dramatically upon binding to the inhibitor. It all comes down to the stretching and non-stretching of the loop between the ligand-binding domain and the ion channel. They're really a series of conformations or events that are happening outside [the cell], and it eventually gets translated to the ion channel activity," said the study leader, Cold Spring Harbor Laboratory (CSHL) Professor Hiro Furukawa.
When glycine and glutamate bind to the NMDA receptor at its ligand-binding domain (LBD), the LBD rolls around, generating a loop that grabs a transmembrane domain. This domain forms the channel through the receptor, so as the LBD rolls, the transmembrane domain, which has been grabbed, is also stretched. This stretching pulls apart the amino acids that form the pore.
This work may help researchers create medications that can control the activity of the NMDA receptor with greater precision. The receptor is thought to play a role in a wide variety of disorders. The study may also help scientists apply the work to other receptors to unlock their mysteries.
