Glutamate signaling

glutamate describe

type 2 nt - amino acid, not made by specific neuron that releases them but packaged into vesicles with transporter unique to that type of neuron (VGLUT), used for excitatory neurotransmission

how is glutamate synthesized

a-ketoglutarate + glutamate dehydrogenase→ glutamate, glutamine + glutaminase → glutamate, a-ketoglutarate + aspartate + aspartate aminotransferase → glutamate

whole cell level

proposed mechanism for regulation of glutamate synthesis - whole cell level - increase neuronal activity = more glucose utilization making pyruvate, then pyruvate processsed in cac = alpha ketoglutarate and is turned into glutamate, not specific to glutamatergic neurons

presynaptic terminal level

neuronal activity = increased intracellular calcium = activate inorganic phosphate transporter, activates mitochondrial glutaminase = increased glutamate, not specific to glutamatergic neurons

how can aat regulate glutamate synthesis

this mechanism is specific to glutamatergic neurons, and is involved in regulating glutamate - variation with aspartate aminotransferase pathway, aat is localized to synaptic vesicles, and blocking aat in glutamatergic neurons reduces loading of glutamate into vesicles

describe glutamate receptors - ionotropic

ampa - glua1-4, excitatory, conduct sodium and potassium, and ca2+ if no glua2, phosphorylation modifies their conductance, needed for learning and memory, glutamate and ampa = agonists

nmda receptors

gluN1, gluN2A-C, gluN3A-B ( reduces conductance), glutamate, nmda, glycine = agonists

kainate receptors

gluK1-5/ gluR5-7, KA1 and KA2, postsynaptic signaling = excitatory transmission, presynaptic signaling regulates gaba release, glutamate and kainic acid = agonists

PKU

mutation in PAH gene = reduced enzyme of phenylaline hydroxylase and accumulation pf phenyalalnice = toxic, diabilities can occur, and treatment = no phenylalanine diet, excess phenylalanine decreases glutamatergic signaling = competes

group 1 metabotropic receptors

mGlur1 and mGlur5, activates phosphoinosital pathways, located postysynaptically, leads to depolarization, regulate sodium and potassium channel function, increases conductance of channels in excitatory manner in glutamatergic neurons, increases GABA released by gabaergic nt in inhibitory manner

group 2

mGlur2 and 3, inhibits cAMP pathway mostly located presynatpically usually inhibit nt reelase, involved in neuroprotection against excitotoxicity, mGluR2 KO mice show increased responsiveness to cocaine

group 3

mGluR4-8, inhibit camp pathway, mostly located presynaptically and usually inhibit nt release, widespread effects in retina, cerebellum, hippocampus, basal ganglia, olfactory bulb, taste buds

glutamate as inhibitory nt in retina

on center bipolar - mGluR6, off center - bipolar cells express iGluRs - ampa and kainate

termination of glutamate signaling

glutamate activate many receptors, with a small amount activating mGluRs, reuptake by presynaptic neuron and neighboring glial cells for recycling/disposal

receptor densensitize

stops the effect of glutamate and other agonists on the receptor

excitotoxicity

too much of a good thing, oxygenated blood = blocked/ narrowed, decreased ATP, atp ase cant work, so intracellular neurons more positive, depolarized neurons = vgcc and glutamatergic neurons release glutamate, excess overstimulates receptors, and calcium influx = enzymes and destroys cells