Excitatory amino acids - Med Chem

How do the structures of the EAA neurotransmitters differ from the inhibitory amino acid neurotransmitters?

EAA neurotransmitters (glutamate, aspartate) are alpha-amino acids containing a carboxylic acid side chain (dicarboxylic acids), whereas inhibitory amino acids like GABA are monocarboxylic acids

What functions do the EAAs perform in the CNS?

Act as excitatory neurotransmitters in the CNS and cause stimulation

Why levels of the EAAs in the CNS are carefully regulated? What is the consequence of having too little glutamate or too much glutamate in the CNS?

Carefully regulated to prevent toxicity: abnormally high glutamate causes seizures and excitotoxic injury, while abnormally low glutamate leads to coma

What happens to the CNS levels of glutamate when a diet rich in glutamate is consumed?

Dietary glutamate (or MSG) does not alter CNS glutamate levels because the blood-brain barrier tightly regulates glutamate entry

What is the major mechanism that operates at the blood brain barrier (BBB) to transport acidic amino acids such as glutamate?

Facilitated diffusion via an acidic amino acid transporter (cannot move against a concentration gradient)

What is the main function of the transporter that operates at the BBB?

To transport excess glutamate out of the CNS

Where does the biosynthesis of the EAAs occur?

In presynaptic neurons (and in presynaptic mitochondria)

What is the process of formation of glutamate from glutamine called? Which bond of glutamine is hydrolyzed to give glutamate? What is the name of the enzyme involved in this process?

Amide hydrolysis; the amide bond (-CONH2) is hydrolyzed; enzyme is glutaminase

What is the process of formation of glutamate from alpha-ketoglutarate and the formation of aspartate from oxaloacetate called? What enzyme is involved in this biosynthetic transformation?

Transamination; catalyzed by transaminase using pyridoxal phosphate (PLP) as a cofactor

Where is glutamate stored after biosynthesis? What is the purpose of storage? How is glutamate transferred to the storage vesicle? Is this process active or passive?

Stored in presynaptic vesicles by VGLUT1; purpose is to maintain a ready neurotransmitter supply and prevent premature degradation; active transport requiring ATP

How is glutamate released from the presynaptic storage site?

Released by exocytosis in response to Ca2+ influx following action potential depolarization of the presynaptic terminal

What are the various subtypes of EAA receptors? Which ones are LGICs? Which ones are GPCRs?

NMDA, Kainate, AMPA, and Quisqualate (Qp); NMDA, Kainate, and AMPA are LGICs; Quisqualate (Qp) is a GPCR

For the LGICs, which ions are transported through these channels?

Na+ and Ca2+

For the GPCR, what are the effector and second messengers?

Effector is Phospholipase C (cleaves PIP2); second messengers are IP3 and DAG

Which NMDA antagonists are currently approved for clinical use? What are they used for?

Namenda (memantine) for Alzheimer's disease, Ketamine as an anesthetic, and Esketamine as an antidepressant

How is EAA neurotransmission terminated? Which is the major mechanism?

Major mechanism is uptake/reuptake into presynaptic neurons and glial cells via EAATs 1-5; secondary mechanism is metabolism in glial cells

How are EAAs terminated by metabolism in the glial cells? Which enzyme is involved and what is the inactivation product?

Glutamate is converted into glutamine by the enzyme glutamine synthetase (glutamine synthase); product is glutamine

How are EAAs involved in ischemia or injury induced cell damage? Outline the steps involved in neuronal damage induced by EAAs.

(1) Energy loss causes cell depolarization -> (2) Triggers excess glutamate release -> (3) Overactivates NMDA receptors causing massive Ca2+ influx -> (4) Disrupted Ca2+ homeostasis and free radicals cause cell death

What are some potential applications of NMDA antagonists?

Trauma from head/spinal injury, epilepsy, Alzheimer's disease, depression, and anesthesia

What is the target and action of Namenda? What disease state is it used to treat?

Non-competitive NMDA receptor antagonist that prevents excitotoxic Ca2+ disruption and destruction of cholinergic neurons; treats Alzheimer's disease

What are the therapeutic uses of ketamine and esketamine?

Ketamine is used as an anesthetic; Esketamine is used as an antidepressant