LectureS 7 + 8 : Amino acid neurotransmitters: Glutamate & GABA

Primary role of Glutamate in the CNS

Glutamate is the main excitatory neurotransmitter in the central nervous system. It plays a crucial role in synaptic plasticity, learning, and memory.

ACTIVATES IONOTROPIC RECEPTORS

Primary role of GABA in the CNS

GABA (γ-aminobutyric acid) is the main inhibitory neurotransmitter in the central nervous system. It reduces neuronal excitability throughout the nervous system.

Distribution and typical neuron type for Glutamate

Glutamate is ubiquitous in the CNS and is mostly found in pyramidal neurones, which are often long-projection neurons connecting different brain regions.

Distribution and typical neuron type for GABA

GABA is found in about 20% of CNS neurons. It is typically located in short, local interneurons, but also in some longer projection neurons.

Describe the Glutamate-Glutamine cycle

Released glutamate is taken up by astrocytes via EAATs.

Inside the astrocyte, glutamine synthase converts it to glutamine.

Glutamine is then transported back to the neuron, where glutaminase converts it back to glutamate for vesicular packaging.

Synthesis of GABA

GABA is synthesized from glutamate via the enzyme glutamic acid decarboxylase (GAD).

Inactivation of GABA

GABA is inactivated by the enzyme GABA-transaminase (GABA-T), which converts it to succinic semialdehyde.

Define Excitatory Postsynaptic Potential (EPSP)

An EPSP is a temporary depolarization of the postsynaptic membrane potential caused by the flow of positive ions (like Na+ and Ca2+) into the postsynaptic cell, as a result of opening ligand-gated ion channels. This makes the neuron more likely to fire an action potential.

Define Inhibitory Postsynaptic Potential (IPSP)

An IPSP is a temporary hyperpolarization of the postsynaptic membrane caused by the flow of negative ions (Cl-) into the cell or positive ions (K+) out of the cell. This makes the neuron less likely to fire an action potential.

Orthosteric vs. Allosteric Modulation

Orthosteric modulation involves a ligand binding to the primary, endogenous agonist binding site on a receptor. Allosteric modulation involves a ligand binding to a different, secondary site on the receptor, which changes the receptor's conformation and modifies its response to the orthosteric ligand.

Structure and function of GABAA receptors

GABAA receptors are ionotropic, pentameric (five subunits) ligand-gated chloride ion channels. GABA binding opens the channel, allowing Cl- influx, causing hyperpolarization and fast synaptic inhibition. They are highly heterogeneous due to multiple subunit isoforms (α, β, γ, δ, ε, ρ).

Key allosteric modulatory sites on the GABAA receptor

The GABAA receptor has multiple allosteric sites, including binding sites for:

1. Benzodiazepines

2. Barbiturates

3. Neurosteroids

4. General anaesthetics (e.g., propofol)

Mechanism of action of Benzodiazepines

Mechanism of action of Benzodiazepines

Answer

Benzodiazepines are positive allosteric modulators of the GABAA receptor. They bind to a site distinct from the GABA binding site and increase the frequency of channel opening in the presence of GABA, enhancing its inhibitory effect.

Structure and function of GABAB receptors

GABAB receptors are metabotropic GPCRs that function as obligate heterodimers (R1 and R2 subunits). Presynaptically, they inhibit neurotransmitter release by closing Ca2+ channels. Postsynaptically, they cause slow hyperpolarization by opening K+ channels.

Clinical application and mechanism of Baclofen

Baclofen is a GABAB receptor agonist used as a muscle relaxant to treat spasticity (e.g., in multiple sclerosis or spinal cord injury). It mimics GABA's inhibitory effects in the spinal cord, reducing the activity of stretch reflex pathways.

Three main families of ionotropic glutamate receptors

• AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors

• Kainate receptors

• NMDA (N-methyl-D-aspartate) receptors

Function of AMPA receptors

AMPA receptors are ionotropic glutamate receptors that mediate fast, excitatory neurotransmission. Upon glutamate binding, they open to allow Na+ influx, causing a rapid depolarization (EPSP) of the postsynaptic membrane.

Unique properties of NMDA receptors

Unique properties of NMDA receptors

Answer

1. Voltage-dependent Mg2+ block at resting potential.

2. Requires co-activation by both glutamate and a co-agonist (glycine or D-serine).

3. High permeability to Ca2+ as well as Na+ and K+.

4. Slower activation and deactivation kinetics compared to AMPA receptors.

Role of the voltage-dependent Mg2+ block in NMDA receptors

At resting membrane potential, a magnesium ion (Mg2+) physically blocks the NMDA receptor channel pore. The channel only opens when the membrane is sufficiently depolarized (e.g., by AMPA receptor activation), which expels the Mg2+ ion, allowing ion flow. This makes the NMDA receptor a 'coincidence detector'.

What is meant by 'excitotoxicity'

Excitotoxicity is the pathological process by which nerve cells are damaged or killed by excessive stimulation by excitatory neurotransmitters like glutamate. It is often mediated by excessive Ca2+ influx through NMDA receptors, leading to the activation of cytotoxic intracellular cascades.

Clinically used drugs that target NMDA receptors

Ketamine: A non-competitive antagonist used as a dissociative anaesthetic and for treatment-resistant depression.

Memantine: A low-affinity, uncompetitive antagonist used to treat moderate-to-severe Alzheimer's disease by reducing excitotoxicity.

Classification of metabotropic glutamate receptors (mGluRs)

mGluRs are classified into three groups based on sequence homology, pharmacology, and intracellular signalling:

Group I (mGluR1, mGluR5): Gq-coupled, increase IP3 and intracellular Ca2+.

Group II (mGluR2, mGluR3): Gi/Go-coupled, inhibit adenylyl cyclase, decrease cAMP.

Group III (mGluR4, mGluR6, mGluR7, mGluR8): Gi/Go-coupled, inhibit adenylyl cyclase, decrease cAMP.

Typical location and function of Group II and Group III mGluRs

Group II and Group III mGluRs are often located presynaptically on nerve terminals, where they function as autoreceptors. Their activation decreases cAMP, leading to reduced Ca2+ influx and a decrease in further glutamate release, acting as a negative feedback mechanism.

Structural reason for Glutamate's ability to bind to many different receptor types

Glutamate is a flexible molecule. Different constituents can rotate along the α-β and β-γ carbon bonds, allowing it to adopt multiple different spatial conformations or 'rotamers'. Each conformation can fit the specific binding pocket of a different receptor subtype.

Main transporters responsible for clearing synaptic glutamate

Excitatory Amino Acid Transporters (EAATs) are responsible for the reuptake of glutamate from the synaptic cleft into both neurons and glial cells (astrocytes), thus terminating its synaptic action