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PSYC 3030 Final: Amino Acid Neurotransmitters I

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PSYC 3030
Boyer Winters

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Amino Acid Neurotransmitters I: Glutamate and Aspartate Excitatory amino acids Most amino acids serve a role in metabolism and protein synthesis, but some are used directly as neurotransmitters Glycine and GABA (inhibitory), glutamate and aspartate (excitatory) Glutamate and Aspartate Most abundant, free, non-essential amino acid in the mammalian brain Synthesized by the body, not required in diet Glutamate is important for metabolism and protein synthesis in all neurons and glia Glutamatergic neurons have higher concentration of glutamate Metabolic and neurotransmitter glutamate are kept separate from one another Amino acids neurotransmitters are used by a large portion of neurons Fast, excitatory neurotransmission via ionotropic receptors Synthesis, Storage, Release, Uptake, Inactivation Synthesis Two possible mechanism 1. Alpha KG Alpha-Ketoglutarate is synthesized from glucose Transanimation by pydridoxal phosphate and alanine aminotransferase moves the amine group from a donor amino acid to the alpha-KG, forming glutamate and a de-aminated amino acid 2. Glutamine Cycle Most neurotransmitter glutamate is synthesized this way Astrocytes and neurons interact to produce glutamate from glutamine Glutamine is converted by glutaminase into glutamate and ammonia Product Inhibition: glutamate and ammonia prevent further production of glutamate by inhibiting glutaminase Storage and Release Glutamate is stored as glutamine (safer) Glutamate is packaged into vesicles by VGLUT1-3: vesicular glutamate transporter 1 OR 2, and/or 3 VGLUTs are selective markers for glutamatergic neurons Uptake EEAT1-5: excitatory amino acid transporters 1 and 2 are on astrocytes 3 is the most widely used Inhibition of 1 or 2 (astrocytes) leads to an increase of synaptic glutamate, but inhibiting 3 does not Inactivation By glutamine synthetase Both astrocytes and neurons Glutamatergic Pathways Cerebral cortex, descending pathways from neocortical pyramidal cells: output neurons, have numerous subcortical projections Cerebellar cortex: parallel fibres, hippocampus Intrahippocampal and hippocampal projection pathways (learning and memory, LTP) Long range and intrinsic projections Cell bodies are not clustered in one area Receptors Ionotropic AMPA Agonized by AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole proprionic acid) and quisqualic acid Antagonized by CNQX and NBQX: sedation, ataxia, reduced brain excitability Sodium and potassium channels Kainate Agonized by kainic acid and domoic acid Antagonized by the same as AMPA receptors, but less so Sodium and potassium channels NMDA Agonized by NMDA (N-methyl-D-aspartic acid) and ibotenic acid Antagonized by CPP and AP-5 (competitive—damages efficacy), and MK-801, PCP, and Ketamine (non-competitive—damages efficacy and potency) Sodium, potassium, and calcium channels (second messenger functions) Metabotropic mGLUR1-7 Use IP3, DAG, and cAMP as second messengers Mostly autoreceptors, negative feedback NMDA Receptor Short-term memory does not require protein synthesis, not reliant on intracellular changes (NMDA receptor is not needed) Calcium eventually leads to protein synthesis NMDA-Dependent-Receptor-Plasticity: increases efficacy of neuronal communication, LTP Increase of Synaptic Weight: externally derived behaviours changes the circuitry of what encoded it in the first place 1) Obligatory orthosteric binding sites for two glutamates 2) Obligatory Co-Agonists: glycine or D-serine, these are almost always present, making glutamate the deciding factor 3) PCP (non-competitive antagonist) allosteric binding site, depressant effects if PCP is bound; also recognizes other non-competitive antagonists (ketamine, MK801) 2+ 2+ 4) Mg binding site, blocks the pore—Ca cannot enter if magnesium is bound Membrane Depolarizes 2+ Mg is normally present in the channel, bound to their site with high affinity at resting potential Depolarization decreases magnesium affinity, leaves the receptor Coincidence Detection The NMDA receptor is only active when two events occur close in time 1) Glutamate is released onto the NMDA receptor
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