Amino Acids As Neurotransmitters In The Cns

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Glutamate (Glu)

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An excitatory amino acid (AA). In the CNS it usually comes from either glucose or glutamine. It is also known as 'home base', which means other AA can be derived from glutamate through enzymatic activity

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Glutamate permeability at different life stages

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In young humans, the BBB has permeability to Glu, and excessive dietary uptake of Glu can be excitotoxic

BBB becomes impermeable to Glu approx. seven days after birth, and

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Glutamine (Gln)

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Glutamate precursor that acts as a reserve source of glutamate, as it has no binding affinity for glutamate receptors

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How is Glu recovered in the CNS

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Released Glu is captured by excitatory AA transporter (EAAT) present on both astrocytes and presynaptic neurons. In the astrocytes Glu is converted to Gln via glutamine synthase. Gln is then transported out of the astrocyte to the neuron via a glutamine transporter (GlnT), where it is converted back to glutamate via glutaminase

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Glu receptor subtypes and brief description

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NMDA, kainate and AMPA - ionotropic, which allows the passage of ions (Na+ and Ca+) through them. Excitatory receptors

Metabotropic receptors (mGluR) are GPCR that are coupled to phosphatidylinositol metabolism. Similar to mACh receptors.

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Two drugs that can cross the BBB

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Ketamine
Memantine

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Ketamine

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non-competitive antagonists at the NMDA receptor. It binds at the same deep site within the ion channel of the NMDA receptor, blocking ion movement. Can also bind to opioid μ receptors as well. This induces a variety of effects including analgesia and anaesthesia

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Phencyclidine (PCP)

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also known as angel dust, has the same mechanism as ketamine and was once used as an anaesthetic agent, but legitimate human use was discontinued when it was found to be responsible for bizarre pyschotic reactions and behaviours in users

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Memeantine

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noncompetitive antagonist on NMDA receptor. Is clinically used in treating moderate to sever confusion (dementia) related to Alzheimer's disease. It may improve memory, awareness, and the ability to perform daily functions

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GABA

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GABA is synthesized from glutamate by the enzyme glutamic acid decarboxylase (GAD), and only GABAergic neurons have GAD, therefore very little GABA can be found outside the CNS

Can be taken up by presynaptic and glial transporters for reuse or degradation by GABA transaminase

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GABA(A) receptors

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Allows inward movement of Cl- ions results in hyperpolarization (IPSP), making it less likely that an AP will occur in the receiving neuron

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Benzodiazepines

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Bind to the g subunit at a modulatory site in GABA(A), which cause a conformational change in the GABA binding site giving it a greater affinity for GABA. The enhanced effect of the agonist results in an increase in inward chloride ion current, while physiologically as anxiolytic and sedative efects

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Barbiturates

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increase pore opening duration in GABA(A) receptors

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GABA(B) receptors

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an obligate heterodimer that is only functional when both GABA(B)R-1 and GABA(B)R-2 are co-expressed in the same cell. When this happens the receptors interact through coiled-coil domains in their carboxyl tails, and they are then expressed on the cell surface, bind to GABA and activate G proteins

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Baclofen

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modulates GABA(B) receptors in the presence of GABA. Presynaptic binding of baclofen hyperpolarizes the membrane, restricting calcium influx into presynaptic terminals and thereby decreasing neurotransmitter release in excitatory spinal pathways, and increasing inhibitory pathway activity

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y-Hydroxybutyric acid (GHB)

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"date rape drug" binds to GABA(B) receptors, causing sedative effects, as well as binding to newly identified GHB receptors which are excitatory in effect, so the net result with GHB is a summative one.

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Glycine

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an inhibitory AA that is derived from Glu via glutamate transaminase (astrocytes). Glycine receptors have an internal chloride channel which allows ions to move down their concentration gradient

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Glycine packaging and release

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presynaptic glycine is packaged into vesicles by the vesicular inhibitory AA transporter (VIAAT) before release

GLyT1: transports Gly into astrocytes
GLyT2: into presynaptic neurons

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strychnine

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a toxin obtained from seeds of an evergreen tree, is a competitive antagonist for glycine receptors, binding the blocking access of glycine to its receptors.

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tetanus toxin

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a toxin that migrates to the CNS and blocks glycine release from interneurons in the spinal cord, resulting in reflex hyperactivity and violent muscle spasms