Glutamate is the major excitatory neurotransmitter. Ionotropic receptors: NMDA (Mg²⁺-blocked at rest, Ca²⁺-permeable on coincident depolarization + glutamate binding — Hebbian "coincidence detector" for LTP), AMPA (fast Na⁺/K⁺ current, primary EPSP carrier), kainate (presynaptic modulation + epileptogenesis). Metabotropic mGlu (Gq or Gi) modulate. Therapeutic targets: NMDA antagonists for depression (ketamine, esketamine — rapid antidepressant via glutamate-burst/BDNF mechanism), Alzheimer's (memantine — moderate-affinity uncompetitive NMDA blocker), and dextromethorphan (low-affinity NMDA antagonist + sigma-1 — DXM/quinidine combo for pseudobulbar affect). ALS: riluzole reduces presynaptic glutamate release + blocks Na⁺ channels. AMPA negative allosteric: perampanel for partial-onset epilepsy. Phencyclidine + ketamine share the NMDA-channel-pore binding site (dissociative phenotype). Glycine + D-serine are NMDA co-agonists at the glycine-B site.
Organ Systems
nervous
Pathway Steps
glutamate → ampa-fast-epsp — via AMPA-R Na⁺/K⁺ current — primary fast excitation. Glutamate, the main excitatory neurotransmitter, activates AMPA receptors to produce the fast excitatory postsynaptic potential — the rapid Na⁺-driven depolarization carrying most moment-to-moment excitatory transmission. AMPA-receptor trafficking is a core mechanism of synaptic plasticity.
glutamate → nmda-ca-influx — via NMDA-R Ca²⁺ influx requires coincident depolarization (Mg²⁺ block release) — LTP signal. Glutamate also activates NMDA receptors, which are both ligand- and voltage-gated (Mg²⁺-blocked at rest) and highly Ca²⁺-permeable. This coincidence detection and calcium influx make NMDA receptors central to LTP and learning — and to excitotoxicity; they are the target of memantine and ketamine.
Known Modulators
ketamine (inhibitor) — NMDA channel pore (uncompetitive). IV/IM dissociative anesthetic; rapid antidepressant (single sub-anesthetic infusion → days of effect); ketamine + analog psychiatric use surging
esketamine (inhibitor) — NMDA channel pore (S-enantiomer of ketamine). intranasal Spravato; treatment-resistant depression + acute suicidality; REMS program (in-clinic observation)