glutamate

Where does glutamate come from?

Synthesized from glucose metabolism through krebs cycle and from the amino acid glutamine via the enzyme glutaminase  The most abundant excitatory neurotransmitter in the brain, produced and recycled in the glutamate-glutamine cycle between neurons and astrocytes

Where does glutamate signal to?

Glutamate signals widely throughout the CNS

Major circuits include: cortico-hippocampal pathways, thalamocortical projections, and corticospinal tracts

Essentially, it is the primary driver of excitatory signaling across cortical and subcortical networks

What does glutamate do?

Glutamate activates ionotropic receptors (AMPA, NMDA, kainate) and metabotropic glutamate receptors (mGluRs)

Functions: Mediates fast excitatory synaptic transmission, Drives synaptic plasticity (LTP, LTD), crucial for learning and memory, Involved in cognition and higher-order brain functions

Cortico-hippocampal circuit 

Composition of AMPA

An AMPA receptor is a tetramer made of four GluA subunits (GluA1–GluA4). Each GluA subunit has 3 transmembrane helices and 1 re-entrant pore loop that helps form the ion channel. The receptor assembles as two pairs of subunits, each pair = a dimer.

Activation of AMPA receptor 

glutamate binding, not voltage dependent

function of AMPA receptor

primary mediator of excitatory synaptic transmission. key role in long term potentiation (LTP); critical for learning and memory

AMPA receptor graph

Illustrates that AMPA receptors behave as simple, linear cation channels: Carry Na⁺ in and K⁺ out, don’t care about voltage (no Mg²⁺ block), critical for fast excitatory transmission.

Perampanel 

AMPA receptor antagonist for epilepsy patients. indicated as adjunctive therapy for partial-onset and primary generalized tonic-clonic seizures. Black-box warnings: psychiatric/behavioural side effects (aggression, hostility, irritability). Mechanism: selective: non-competitive AMPA antagonist. Believed to act as a negative allosteric modulator (NAM)

NMDA receptor composition

heterotetramer (4 subunits, usually: 2 GluN1 + 2 GluN2 or GluN3). Each subunit: 3 TM helics + one re-entrant pore loop. 

NMDA receptor activation

1) glutamate binding at the orthosteric site. 2) glysine (or D-serine) binding 3) postsynaptic depolarization; relieves Mg block. Once open, NMDA channels allow NA and Ca infulx and K efflux.

What does the current–voltage (I–V) relationship of the NMDA receptor look like with and without Mg²⁺ present?

Without Mg²⁺: Nearly linear I–V curve. Channel conducts Na⁺ and Ca²⁺ inward, K⁺ outward, when glutamate + glycine bind.

With Mg²⁺ : Non-linear, “J-shaped” I–V curve. At hyperpolarized potentials (e.g., –80 mV): Mg²⁺ ions block the pore, preventing current. At depolarized potentials (above ~ –40 mV): Mg²⁺ is expelled → channel opens → strong inward current.

Key concept: NMDA receptors are coincidence detectors. They only open when glutamate is present AND the postsynaptic cell is depolarized, making them essential for synaptic plasticity (LTP).

NMDA function and overactivation

Activated in parallel with AMPA receptors. Facilitates Ca-dependednt signaling → activates cascades: CaMKII phosphoylation of AMPA receptors, leading to LTP. BDNF release → promotes plasticity.

Function: learning, memory, cognition

Overactivation: excitotoxicity (cell death), psychiatric/mood disorders

NMDA excitotoxicity

excessive Va influx → neurotoxicity. implicated in: ischemic stokr, traumatic brain injury, all neurodegenerative diseases (AD, PD, HD)

memantine 

NMDA antagonist for AD. low affinity open channel blocker (non-competitive to agonist sites). blocks open channel in the presence of agonists (activated receptor). believed to selectively block pathological activatin of NMDA receptors, ex. that mediated by elevated tonic levels of glutamate. 

ketamine

NMDA antagonist for anaesthetics. potential for caridac stimulation and respiratory depression. potential for psychoactive effects (ex. dissociation) “special K”. new indication for treatment-reisstant depression, S enantiomer formulated as asketamine nasal spary. high affinity open channel blocker (noncompetitive to agonist sites). blocks open channel in the presence of agonists (activated receptor)

metabotropic glutamate receptors

GPCRs: jas 7 TM domains; functions as dimers

activated by: glutamate

function: depends on linked G protein and effectors present in nature.

• Gi: βγ activates GIRK

• Gq: activates PLC → PIP2 hydrolysis → affects KCNQ channels

Broader effect: modulates excitability, plasticity, and synaptic signaling

mGluRs in drug development

Review: standsley and conn, 2019

Most potential indications still experimental

Example: mGluR5 drug (Basimglurant)

Negative allosteric modulator (NAM)

Investigated for depression and trigeminal neuralgia