Glutamate Neurotransmitter PDF

1. Glutamate SL22051 - Pharmacology of the Central Nervous System Key Information Amino acid neurotransmitter Synthesised from Glutamine Main excitatory neurotransmitter of the CNS Activates Ionotropic (ion-channel) receptors G protein coupled receptors Receptor Types Reuptake is reg...

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Glutamate SL22051 - Pharmacology of the Central Nervous System Key Information Amino acid neurotransmitter Synthesised from Glutamine Main excitatory neurotransmitter of the CNS Activates Ionotropic (ion-channel) receptors G protein coupled receptors Receptor Types Reuptake is regulated by Excitatory Amino Acid Transporters (EAAT) Ca2+ influx into the presynaptic terminal in response to depolarisation by an action potential causes vesicle fusing and neurotransmitter release into the synaptic cleft. Glutamate Synthesis and Recycling Glutamine produced in glial cells Transported in and out of nerve cells via glutamine transporters in cell membrane Glutamine that has been transported into the cell is acted on by phosphate activated Glutaminase, converting it to Glutamate Glutamate stored in vesicles until stimulated by cell activity, causing binding to cell membrane, releasing Glutamate into synaptic cleft Once released, Glutamate binds with post-synaptic receptors After action on post-synaptic neurone is complete, Glutamate molecules undergo reuptake, either: To glial cells, where they are converted back to glutamine by glutamine synthase for storage  To presynaptic vesicle, where they are repackaged into vesicles to continue the cycle Glutamate receptors are either ionotropic (ion channel) or metabotropic (GPCR). Glutamate has different effects depending on the type of receptor. AMPA Receptors Can be homomeric or heteromeric, containing GluA1, A2, A3, or A4 subunits. Pharmacology Key Definitions Located at the post-synaptic membrane of excitatory synapses, AMPA activation causes rapid membrane depolarisation upon binding of glutamate, due to opening of channel allowing a rapid influx of Na+ and release of K+. Catagorised as excitatory receptors, they generate an action potential when the membrane potential reaches a threshold Dual Gating Seen in NMDA receptors, dual gating requires activation by voltage (in the form of cell membrane depolarisation caused by AMPA) and ligand binding to allow transport of molecules through the channel NMDA Receptor Heteromeric, voltage gated and ligand gated receptors. They generate an action potential once the threshold potential has been reached AMPA activation typically allows for depolarisation of the membrane, allowing Mg2+ ions to dissociate and 'unblock' the channel The unblocking of Mg2+ allows Ca2+ and Na+ ions to flow through channel and further depolarises the membrane, but slower than AMPA EPSP is the Excitatory Post-Synaptic Potential, which is initiated by stimulation of the post-synaptic neurone. AMPA EPSP is faster than NMDA EPSP. Activation of NMDA and AMPA at the same time can give a compounded EPSP, and frequency of these activations augments the shape of the EPSP curve. Metabotropic Glutamate Receptors Second messenger systems, so don't mediate fast synaptic transmission as with Ionotropic receptors, but rather play a slower neuromodulating role, and also regulate ion channels. Found on pre- and post-synaptic neurones, as well as glial cells. mGluR typically work with G proteins to close usually open Ca2+ channels, so less Ca2+ enters the cell. This is a mechanism to control neurotransmitter release. The G protein B/y subunit interacts with Ca2+ channels. This reduces vesicle binding and subsequently neurotransmitter release into the synaptic cleft. This is how signal transmission can be regulated by mGluRs. Conversely, K+ channels typically are open to allow efflux of K+. mGluR can work with G proteins in the same way to block the efflux. This leads to slow depolarisation of the membrane.  G protein a-subunit can be liberated fron the B/y subunit. This action causes an activation of Phospholipase C, causing a release of IP3. This release results in a second messenger cascade that leads to release of Ca2+ from intracellular stores of the ER. This can have effects on further enzyme activation, regulation of ion channels, and modulation of postsynaptic excitability. However, excessive release of Ca2+ can be neurotoxic. Controlling Glutamate Release Levels Neurotransmitters are released into the synaptic cleft to bind to postsynaptic neurone. There are also receptors on presynaptic neurone to monitor and modify neurotransmitter levels This is an important mechanism in preventing excitotoxicity. Summary Glutamate is the main excitatory neurotransmitter in the CNS, synthesized from glutamine in glial cells and recycled via the glutamate-glutamine cycle. It activates two types of receptors: ionotropic (AMPA, NMDA) and metabotropic (mGluRs). AMPA Receptors: Mediate rapid excitatory transmission by allowing Na⁺ influx and K⁺ efflux, causing fast depolarization. NMDA Receptors: Require both glutamate binding and depolarization (via AMPA activation) to unblock Mg²⁺, enabling slower Ca²⁺ and Na⁺ influx critical for synaptic plasticity. mGluRs: Regulate synaptic activity through second-messenger systems, modulating ion channels and neurotransmitter release to prevent excitotoxicity. Tight regulation of glutamate release and receptor activation ensures proper neural signaling and avoids neurotoxicity, maintaining CNS function.